5-173234786-G-T

Position:

chr5-173234786-G-T

Variant summary

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

The ENST00000329198.5(NKX2-5):c.298C>A(p.Pro100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,570,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P100A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

NKX2-5
ENST00000329198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.16

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=0.09879169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NKX2-5	NM_004387.4 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2	1	NM_004387.4	ENSP00000327758	P1	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2	1		ENSP00000395378		P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2	2		ENSP00000427906		P52952-2
NKX2-5	ENST00000517440.1 linkuse as main transcript	c.298C>A	p.Pro100Thr	missense_variant	1/2	4		ENSP00000429905

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000145

AC:

AN:

207084

Hom.:

AF XY:

0.0000177

AC XY:

AN XY:

112948

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000633

Gnomad SAS exome

AF:

0.0000855

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000776

AC:

AN:

1418310

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

702480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.0000502

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Sep 29, 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. ClinVar contains an entry for this variant (Variation ID: 578303). 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. This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the NKX2-5 protein (p.Pro100Thr). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2024

The p.P100T variant (also known as c.298C>A), located in coding exon 1 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 298. The proline at codon 100 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Benign

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.099

T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.90

L;L;L;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.32

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.60

T;T;T;T

Sift4G

Benign

0.65

T;T;T;.

Polyphen

0.0

B;.;.;B

Vest4

0.12

MutPred

0.16

Gain of phosphorylation at P100 (P = 0.0167);Gain of phosphorylation at P100 (P = 0.0167);Gain of phosphorylation at P100 (P = 0.0167);Gain of phosphorylation at P100 (P = 0.0167);

MVP

0.57

MPC

0.57

ClinPred

0.037

GERP RS

0.25

Varity_R

0.056

gMVP

0.33

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