5-173233053-G-T

Variant names:

• chr5-173233053-G-T
• rs1554093487
• NM_004387.4:c.491C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004387.4(NKX2-5):​c.491C>A​(p.Ser164*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S164S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKX2-5 NM_004387.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.97
• Publications: 0 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 18 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 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173233053-G-T is Pathogenic according to our data. Variant chr5-173233053-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 519074.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.491C>A	p.Ser164*	stop_gained	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*290C>A		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*444C>A		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.491C>A	p.Ser164*	stop_gained	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.*444C>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.*290C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451904 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 721604

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 43074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39276

South Asian (SAS) AF: 0.00 AC: 0 AN: 85178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5366

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107908

Other (OTH) AF: 0.00 AC: 0 AN: 59984

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial septal defect 7 Pathogenic:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser164*) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital heart disease (PMID: 32369864). ClinVar contains an entry for this variant (Variation ID: 519074). This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Cardiovascular phenotype Pathogenic:1

Jul 17, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S164* pathogenic mutation (also known as c.491C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 491. This changes the amino acid from a serine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation. Truncating variants in the NKX2-5 gene are well-reported as disease-causing in individuals with septal defects and atrioventricular block (Schott JJ et al. Science, 1998 Jul;281:108-11; Benson DW et al. J. Clin. Invest., 1999 Dec;104:1567-73). As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.94
GERP RS		4.1
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: rs1554093487; hg19: chr5-172660056;