rs137852684
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2
The NM_004387.4(NKX2-5):c.355G>T(p.Ala119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,601,352 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A119V) has been classified as Likely benign.
Frequency
Consequence
NM_004387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.355G>T | p.Ala119Ser | missense_variant | 2/2 | ENST00000329198.5 | |
NKX2-5 | NM_001166175.2 | c.*308G>T | 3_prime_UTR_variant | 2/2 | |||
NKX2-5 | NM_001166176.2 | c.*154G>T | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.355G>T | p.Ala119Ser | missense_variant | 2/2 | 1 | NM_004387.4 | P1 | |
NKX2-5 | ENST00000424406.2 | c.*308G>T | 3_prime_UTR_variant | 2/2 | 1 | ||||
NKX2-5 | ENST00000521848.1 | c.*154G>T | 3_prime_UTR_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000775 AC: 118AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000904 AC: 209AN: 231088Hom.: 2 AF XY: 0.00109 AC XY: 139AN XY: 127244
GnomAD4 exome AF: 0.000739 AC: 1071AN: 1449008Hom.: 6 Cov.: 35 AF XY: 0.000822 AC XY: 593AN XY: 721090
GnomAD4 genome ? AF: 0.000775 AC: 118AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74502
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | NKX2-5: PM5, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2020 | This variant is associated with the following publications: (PMID: 23285148, 24376681, 23661673, 27207958, 16418214, 28387797, 28798025, 31147515) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hypothyroidism, congenital, nongoitrous, 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2006 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2018 | Variant summary: NKX2-5 c.355G>T (p.Ala119Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 259522 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 194.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease phenotype (5e-06), strongly suggesting that the variant is benign. The variant, c.355G>T has been reported in the literature in individuals affected with Congenital Heart Disease, and the same publication reports experimental evidence evaluating an impact on protein function that showed variant behaves equal to wildtype NKX2-5 (vanEngelen_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
NKX2-5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Atrial septal defect 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at