5-173232621-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004387.4(NKX2-5):c.923T>C(p.Ile308Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,461,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I308V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

Variant links:

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]

NKX2-5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2562899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NKX2-5	NM_004387.4 linkuse as main transcript	c.923T>C	p.Ile308Thr	missense_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2 linkuse as main transcript	c.*876T>C		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2 linkuse as main transcript	c.*722T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.923T>C	p.Ile308Thr	missense_variant	2/2	1	NM_004387.4	P1	P52952-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250204

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1461176

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrial septal defect 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2022

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. 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. This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. This variant is present in population databases (rs771088497, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 308 of the NKX2-5 protein (p.Ile308Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Benign

0.89

DEOGEN2

Benign

0.30

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.010

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.77

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.44

REVEL

Benign

0.21

Sift

Benign

0.39

Sift4G

Benign

0.42

Polyphen

0.037

Vest4

0.33

MutPred

0.29

Loss of stability (P = 0.0127);

MVP

0.65

MPC

0.63

ClinPred

0.34

GERP RS

4.3

Varity_R

0.093

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over