rs587784066

Positions:

• chr5-173233071-TTG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004387.4(NKX2-5):​c.471_472del​(p.Phe157LeufsTer94) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.25

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 Pathogenic. Variant got 12 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 93 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173233071-TTG-T is Pathogenic according to our data. Variant chr5-173233071-TTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 159255.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.471_472del	p.Phe157LeufsTer94	frameshift_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166175.2	c.*424_*425del		3_prime_UTR_variant	2/2		NP_001159647.1
NKX2-5	NM_001166176.2	c.*270_*271del		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	c.471_472del	p.Phe157LeufsTer94	frameshift_variant	2/2	1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.*424_*425del		3_prime_UTR_variant	2/2	1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.*270_*271del		3_prime_UTR_variant	2/2	2		ENSP00000427906

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Malformation of the heart and great vessels Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Computational scores

Source: dbNSFP v4.3

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: rs587784066; hg19: chr5-172660074;