NM_001080517.3(SETD5):c.960-5C>G AND Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 19, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001726503.3

Allele description [Variation Report for NM_001080517.3(SETD5):c.960-5C>G]

NM_001080517.3(SETD5):c.960-5C>G

Gene:

SETD5:SET domain containing 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_001080517.3(SETD5):c.960-5C>G

HGVS:

NC_000003.12:g.9442123C>G
NG_034132.1:g.49424C>G
NM_001080517.3:c.960-5C>GMANE SELECT
NM_001292043.2:c.666-5C>G
NM_001349451.2:c.666-5C>G
NC_000003.11:g.9483807C>G
NM_001080517.1:c.960-5C>G
NM_001080517.2:c.960-5C>G

Links:

dbSNP: rs2125193661

NCBI 1000 Genomes Browser:

rs2125193661

Molecular consequence:

NM_001080517.3:c.960-5C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001292043.2:c.666-5C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001349451.2:c.666-5C>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (MRD23)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 23
Identifiers:: MONDO: MONDO:0014336; MedGen: C3810406; Orphanet: 404440; OMIM: 615761

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001571491	Kids Neuroscience Centre, Sydney Children's Hospitals Network	criteria provided, single submitter (Bournazos AM et al. (Genet Med 2021))	Likely pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766666	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28905509, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001571491

Kids Neuroscience Centre, Sydney Children's Hospitals Network

criteria provided, single submitter

(Bournazos AM et al. (Genet Med 2021))

Likely pathogenic

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002766666

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 19, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

Bournazos AM, Riley LG, Bommireddipalli S, Ades L, Akesson LS, Al-Shinnag M, Alexander SI, Archibald AD, Balasubramaniam S, Berman Y, Beshay V, Boggs K, Bojadzieva J, Brown NJ, Bryen SJ, Buckley MF, Chong B, Davis MR, Dawes R, Delatycki M, Donaldson L, Downie L, et al.

Genet Med. 2022 Jan;24(1):130-145. doi: 10.1016/j.gim.2021.09.001. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906502

De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus.

Green C, Willoughby J; DDD Study., Balasubramanian M.

Am J Med Genet A. 2017 Dec;173(12):3165-3171. doi: 10.1002/ajmg.a.38461. Epub 2017 Sep 14.

PubMed [citation]

PMID:: 28905509

See all PubMed Citations (3)

Details of each submission

From Kids Neuroscience Centre, Sydney Children's Hospitals Network, SCV001571491.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The c.960-5C>G variant induces exon 10 skipping (p.(Pro321Cysfs*4)) causing a frameshift, encoding 4 missense amino acids and a premature termination codon. These transcripts are predicted to be targeted for nonsense-mediated decay. Any mis-spliced SETD5 transcripts with exon 10 skipping that escape nonsense-mediated decay encode SETD5 proteins missing 1121 amino acids (p.(Pro321_Ser1442del)) from the C-terminus.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	Whole blood	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766666.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (intron 19 of 22) (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been proven to result in aberrant splicing resulting in out-of-frame exon 10 skipping, p.(Pro321Cysfs*4) (Splicing Diagnostics, Kid’s Neuroscience Centre) (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0508 – In silico predictions for abnormal splicing are conflicting. (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD predicted variants have been reported as pathogenic in patients with SETD5-related intellectual disability (ClinVar, PMID: 28905509) (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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