NM_004387.4:c.768T>G

Variant names:

• chr5-173232776-A-C
• rs104893907
• NM_004387.4:c.768T>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004387.4(NKX2-5):​c.768T>G​(p.Tyr256*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y256Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.21
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• atrial septal defect 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• hypothyroidism, congenital, nongoitrous, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• NKX2.5-related congenital, conduction and myopathic heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tetralogy of fallot

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• conotruncal heart malformations

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated congenital asplenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173232776-A-C is Pathogenic according to our data. Variant chr5-173232776-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 254163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.768T>G	p.Tyr256*	stop_gained	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*567T>G		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*721T>G		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.768T>G	p.Tyr256*	stop_gained	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.*721T>G		downstream_gene_variant		1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.*567T>G		downstream_gene_variant		2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Pathogenic:1

Jan 01, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.068
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		1.2
Vest4		0.72
GERP RS		-0.45
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893907; hg19: chr5-172659779;