5-173232508-C-A

Variant names:

• chr5-173232508-C-A
• rs703752
• NM_004387.4:c.*61G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004387.4(NKX2-5):​c.*61G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,589,370 control chromosomes in the GnomAD database, including 96,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7485 hom., cov: 33)
  • Exomes 𝑓: 0.35 (89051 hom.)
• Consequence: NKX2-5 NM_004387.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.816
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-173232508-C-A is Benign according to our data. Variant chr5-173232508-C-A is described in ClinVar as [Benign]. Clinvar id is 211668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.*61G>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*835G>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*989G>T		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.*61G>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46560 AN: 152124 Hom.: 7474 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.348 AC: 500047 AN: 1437128 Hom.: 89051 Cov.: 42 AF XY: 0.350 AC XY: 250238 AN XY: 714484

African (AFR) AF: 0.268 AC: 8950 AN: 33376

American (AMR) AF: 0.242 AC: 10357 AN: 42764

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8059 AN: 25932

East Asian (EAS) AF: 0.0748 AC: 2943 AN: 39366

South Asian (SAS) AF: 0.399 AC: 33940 AN: 85092

European-Finnish (FIN) AF: 0.302 AC: 11522 AN: 38186

Middle Eastern (MID) AF: 0.363 AC: 2040 AN: 5618

European-Non Finnish (NFE) AF: 0.363 AC: 402334 AN: 1106902

Other (OTH) AF: 0.332 AC: 19902 AN: 59892

GnomAD4 genome AF: 0.306 AC: 46597 AN: 152242 Hom.: 7485 Cov.: 33 AF XY: 0.300 AC XY: 22323 AN XY: 74422

African (AFR) AF: 0.269 AC: 11201 AN: 41564

American (AMR) AF: 0.260 AC: 3969 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3470

East Asian (EAS) AF: 0.0583 AC: 301 AN: 5162

South Asian (SAS) AF: 0.378 AC: 1825 AN: 4822

European-Finnish (FIN) AF: 0.262 AC: 2782 AN: 10606

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24399 AN: 68002

Other (OTH) AF: 0.305 AC: 645 AN: 2116

Alfa AF: 0.340 Hom.: 28563

Bravo AF: 0.300

Asia WGS AF: 0.240 AC: 839 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.6
DANN	Benign	0.72
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs703752; hg19: chr5-172659511; COSMIC: COSV61298801; COSMIC: COSV61298801;