NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter) AND Dyskeratosis congenita, digenic

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 22, 2022
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV002285189.1

Allele description [Variation Report for NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)]

NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)

Genes:

ENOSF1:enolase superfamily member 1 [Gene - OMIM - HGNC]
TYMS:thymidylate synthetase [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

18p11.32

Genomic location:

Preferred name:

NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)

HGVS:

NC_000018.10:g.669151_669152insTG
NG_028255.1:g.16548_16549insTG
NM_001071.4:c.534_535insTGMANE SELECT
NM_001354867.2:c.455-1541_455-1540insTG
NM_001354868.2:c.285_286insTG
NP_001062.1:p.Met179Ter
NP_001341797.1:p.Met96Ter
LRG_783:g.16548_16549insTG
NC_000018.9:g.669151_669152insTG

Protein change:

M179*

Links:

OMIM: 188350.0003; dbSNP: rs2144335824

NCBI 1000 Genomes Browser:

rs2144335824

Molecular consequence:

NM_001354867.2:c.455-1541_455-1540insTG - intron variant - [Sequence Ontology: SO:0001627]
NM_001071.4:c.534_535insTG - nonsense - [Sequence Ontology: SO:0001587]
NM_001354868.2:c.285_286insTG - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Dyskeratosis congenita, digenic (DKCD)
Identifiers:: MONDO: MONDO:0031057; MedGen: C5774217; OMIM: 620040

Recent activity

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Homo sapiens ST18 C2H2C-type zinc finger transcription factor (ST18), transcript...
Homo sapiens ST18 C2H2C-type zinc finger transcription factor (ST18), transcript variant 12, mRNA
gi|1890261494|ref|NM_001352836.2|

Nucleotide
Homo sapiens interferon alpha inducible protein 27 like 1 (IFI27L1), transcript ...
Homo sapiens interferon alpha inducible protein 27 like 1 (IFI27L1), transcript variant 1, mRNA
gi|1676317924|ref|NM_145249.3|

Nucleotide
Chain A, MOSUB1 TRANSCRIPTION COFACTOR
Chain A, MOSUB1 TRANSCRIPTION COFACTOR
gi|635576621|pdb|4BHM|A

Protein
DUF2570 domain-containing protein [Escherichia coli]
DUF2570 domain-containing protein [Escherichia coli]
gi|1246084640|ref|WP_096282701.1|

Protein
PREDICTED: Phyllostomus discolor lysine demethylase 2B (KDM2B), transcript varia...
PREDICTED: Phyllostomus discolor lysine demethylase 2B (KDM2B), transcript variant X5, mRNA
gi|1899630465|ref|XM_036014586.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002574904	OMIM	no assertion criteria provided	Pathogenic (Sep 22, 2022)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002574904

OMIM

no assertion criteria provided

Pathogenic
(Sep 22, 2022)

germline

literature only

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita.

Tummala H, Walne A, Buccafusca R, Alnajar J, Szabo A, Robinson P, McConkie-Rosell A, Wilson M, Crowley S, Kinsler V, Ewins AM, Madapura PM, Patel M, Pontikos N, Codd V, Vulliamy T, Dokal I.

Am J Hum Genet. 2022 Aug 4;109(8):1472-1483. doi: 10.1016/j.ajhg.2022.06.014. Erratum in: Am J Hum Genet. 2024 Jul 11;111(7):1494. doi: 10.1016/j.ajhg.2024.05.022.

PubMed [citation]

PMID:: 35931051
PMCID:: PMC9388389

Details of each submission

From OMIM, SCV002574904.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sibs (family 4) with digenic dyskeratosis congenita (DKCD; 620040), Tummala et al. (2022) identified a heterozygous 2-bp insertion (c.534_535insTG, NM_001071.4) in the TYMS gene, resulting in a frameshift and premature termination (Met179Ter). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father. The sibs also carried a common haplotype in the ENOSF1 gene that was inherited from the unaffected mother who did not have the TYMS mutation. This C-A-ins haplotype (rs699517, rs2790, and rs11280056) had been associated with both reduced TYMS and increased ENOSF1 expression. Sequencing also identified a heterozygous variant in intron 1 of the TYMSOS (TYMS opposite strand) gene in both sibs that was inherited from the unaffected mother (MAF of 0.00026 in gnomAD) and may have influenced the phenotype.

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

Last Updated: Dec 24, 2023

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