Variant 5-173233083-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_004387.4(NKX2-5):c.461A>G(p.Glu154Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.99

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity NKX25_HUMAN there are 47 pathogenic changes around while only 0 benign (100%) in NM_004387.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 5-173233083-T-C is Pathogenic according to our data. Variant chr5-173233083-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 156158.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-173233083-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NKX2-5	NM_004387.4 linkuse as main transcript	c.461A>G	p.Glu154Gly	missense_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166175.2 linkuse as main transcript	c.*414A>G		3_prime_UTR_variant	2/2		NP_001159647.1
NKX2-5	NM_001166176.2 linkuse as main transcript	c.*260A>G		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 linkuse as main transcript	c.461A>G	p.Glu154Gly	missense_variant	2/2	1	NM_004387.4	ENSP00000327758	P1	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.*414A>G		3_prime_UTR_variant	2/2	1		ENSP00000395378		P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.*260A>G		3_prime_UTR_variant	2/2	2		ENSP00000427906		P52952-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Atrial septal defect 7

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Nemer Genomics and Translation Biomedicine Lab, American University of Beirut

Jan 01, 2014

Familial Atrial Septal defect Secundum type with progressive atrioventricular block -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.86

Vest4

0.97

MutPred

0.74

Loss of ubiquitination at K158 (P = 0.0288);

MVP

0.98

MPC

1.5

ClinPred

1.0

GERP RS

4.2

Varity_R

0.98

gMVP

0.76

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