rs201582515
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The ENST00000329198.5(NKX2-5):c.448G>A(p.Val150Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000163 in 1,599,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V150V) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
NKX2-5
ENST00000329198.5 missense
ENST00000329198.5 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 6.14
Genes affected
NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000329198.5
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.448G>A | p.Val150Ile | missense_variant | 2/2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166175.2 | c.*401G>A | 3_prime_UTR_variant | 2/2 | NP_001159647.1 | |||
NKX2-5 | NM_001166176.2 | c.*247G>A | 3_prime_UTR_variant | 2/2 | NP_001159648.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.448G>A | p.Val150Ile | missense_variant | 2/2 | 1 | NM_004387.4 | ENSP00000327758 | P1 | |
NKX2-5 | ENST00000424406.2 | c.*401G>A | 3_prime_UTR_variant | 2/2 | 1 | ENSP00000395378 | ||||
NKX2-5 | ENST00000521848.1 | c.*247G>A | 3_prime_UTR_variant | 2/2 | 2 | ENSP00000427906 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000166 AC: 24AN: 1447050Hom.: 0 Cov.: 35 AF XY: 0.0000209 AC XY: 15AN XY: 718870
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74504
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atrial septal defect 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 150 of the NKX2-5 protein (p.Val150Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with transposition of the great arteries (PMID: 19933292). ClinVar contains an entry for this variant (Variation ID: 518495). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NKX2-5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 18, 2022 | - - |
Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C2673630:Hypothyroidism, congenital, nongoitrous, 5;C3276096:Atrial septal defect 7;C3280785:Ventricular septal defect 3;C3280795:Hypoplastic left heart syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2015 | The p.V150I variant (also known as c.448G>A), located in coding exon 2 of the NKX2-5 gene, results from a G to A substitution at nucleotide position 448. The valine at codon 150 is replaced by isoleucine, an amino acid with highly similar properties. This variant was described in an individual with multiple ventricular septal defects, who also harbored another genetic alteration in ZIC3 (De Luca A et al. Heart. 2010;96(9):673-7). This variant was previously reported in the SNPDatabase as rs201582515. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.51% (1/196) Tuscan alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at