5-173232508-C-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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. Variant chr5-173232508-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.*61G>T		3_prime_UTR_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.*989G>T		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2	c.*835G>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.*61G>T		3_prime_UTR_variant	2/2	1	NM_004387.4	P1

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

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.0748

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.332

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

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.0583

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.305

Alfa AF: 0.341 Hom.: 11982

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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.6
Dann	Benign	0.72

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