NM_017951.5(SMPD4):c.-43del AND Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 21, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002472159.2

Allele description [Variation Report for NM_017951.5(SMPD4):c.-43del]

NM_017951.5(SMPD4):c.-43del

Gene:

SMPD4:sphingomyelin phosphodiesterase 4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q21.1

Genomic location:

Preferred name:

NM_017951.5(SMPD4):c.-43del

HGVS:

NC_000002.12:g.130176636del
NG_053070.1:g.11116del
NM_001171083.2:c.75del
NM_017751.4:c.75del
NM_017951.5:c.-43delMANE SELECT
NP_001164554.1:p.Trp25fs
NP_060221.2:p.Trp25fs
NC_000002.11:g.130934209del
NM_017951.4:c.75delG
NR_033230.2:n.1223delG
NR_033231.3:n.76del
NR_033232.3:n.76del

Protein change:

W25fs

Molecular consequence:

NM_017951.5:c.-43del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001171083.2:c.75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_017751.4:c.75del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_033231.3:n.76del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_033232.3:n.76del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
Identifiers:: MONDO: MONDO:0032838; MedGen: C5231431; OMIM: 618622

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768620	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31495489, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768620

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 21, 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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E, van der Ent M, Palombo F, Lequin MH, Dremmen M, de Wit MCY, Severino M, Divizia MT, Striano P, Ordonez-Herrera N, Alhashem A, Al Fares A, Al Ghamdi M, Rolfs A, Bauer P, Demmers J, Verheijen FW, et al.

Am J Hum Genet. 2019 Oct 3;105(4):689-705. doi: 10.1016/j.ajhg.2019.08.006. Epub 2019 Sep 5.

PubMed [citation]

PMID:: 31495489
PMCID:: PMC6817560

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768620.1

#	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_v0.6.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (P) 0304 - Variant is present in gnomAD <0.01 for recessive indication. (P) 0404 - Variant is located in a gene associated with a severe early onset RECESSIVE condition that is TOLERANT to bi-allelic loss-of-function variants. (B) 0702 – Multiple comparable variants also predicted to cause NMD, have strong previous evidence for pathogenicity (PMID:31495489). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No published segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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