rs3729753

Positions:

• chr5-173232938-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004387.4(NKX2-5):​c.606G>C​(p.Leu202Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,605,268 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (361 hom.)
• Consequence: NKX2-5 NM_004387.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.22

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-173232938-C-G is Benign according to our data. Variant chr5-173232938-C-G is described in ClinVar as [Benign]. Clinvar id is 159256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173232938-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.606G>C	p.Leu202Leu	synonymous_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*405G>C		3_prime_UTR_variant	2/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*559G>C		3_prime_UTR_variant	2/2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.606G>C	p.Leu202Leu	synonymous_variant	2/2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406	c.*559G>C		3_prime_UTR_variant	2/2	1		ENSP00000395378.2
NKX2-5	ENST00000521848	c.*405G>C		3_prime_UTR_variant	2/2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152236 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00986 AC: 2250 AN: 228218 Hom.: 78 AF XY: 0.0118 AC XY: 1476 AN XY: 125230

Gnomad AFR exome AF: 0.0000746

Gnomad AMR exome AF: 0.0000927

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.0345

Gnomad SAS exome AF: 0.0536

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000199

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00558 AC: 8105 AN: 1452914 Hom.: 361 Cov.: 35 AF XY: 0.00684 AC XY: 4940 AN XY: 722352

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.000208

Gnomad4 ASJ exome AF: 0.00100

Gnomad4 EAS exome AF: 0.0819

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000640

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152354 Hom.: 17 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74512

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0490

Gnomad4 SAS AF: 0.0565

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000934 Hom.: 2

Bravo AF: 0.00156

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Atrial septal defect 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.95

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: rs3729753; hg19: chr5-172659941;