rs771533553

chr5-173232936-T-Cchr5-173232936-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004387.4(NKX2-5):c.608A>G(p.Glu203Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,452,522 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. E203E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.608A>G	p.Glu203Gly	missense_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.*561A>G		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2	c.*407A>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.608A>G	p.Glu203Gly	missense_variant	2/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.*561A>G		3_prime_UTR_variant	2/2	1
NKX2-5	ENST00000521848.1	c.*407A>G		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000308 AC: 7 AN: 227236 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 124856

Gnomad AFR exome AF: 0.0000752

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000297

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1452522 Hom.: 0 Cov.: 35 AF XY: 0.00000554 AC XY: 4 AN XY: 722180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000333 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial septal defect 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2023

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. This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 203 of the NKX2-5 protein (p.Glu203Gly). This variant is present in population databases (rs771533553, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 19678963, 21091212). ClinVar contains an entry for this variant (Variation ID: 519328). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NKX2-5 protein function. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2016

The p.E203G variant (also known as c.608A>G), located in coding exon 2 of the NKX2-5 gene, results from an A to G substitution at nucleotide position 608. The glutamic acid at codon 203 is replaced by glycine, an amino acid with some similar properties. This alteration has been previously reported in subjects with congenital heart disease (Hamanoue H et al. Cardiol Young, 2009 Sep;19:482-5; Dinesh SM et al. Genet Test Mol Biomarkers, 2010 Dec;14:873-9). Based on data from ExAC, the G allele has an overall frequency of <0.01% (4/71849). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.53
MutPred		0.19		Loss of stability (P = 0.059);
MVP		0.86
MPC		0.96
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771533553; hg19: chr5-172659939;