5-173233001-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004387.4(NKX2-5):c.543G>A(p.Gln181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,611,374 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (61 hom.)
• Consequence: NKX2-5 NM_004387.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.37

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=-0.45).
• BP6: Variant 5-173233001-C-T is Benign according to our data. Variant chr5-173233001-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173233001-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00601 (916/152350) while in subpopulation AMR AF= 0.0113 (173/15308). AF 95% confidence interval is 0.00993. There are 8 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.543G>A	p.Gln181=	synonymous_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.*496G>A		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2	c.*342G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.543G>A	p.Gln181=	synonymous_variant	2/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.*496G>A		3_prime_UTR_variant	2/2	1
NKX2-5	ENST00000521848.1	c.*342G>A		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152232 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00689

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00748 AC: 1836 AN: 245362 Hom.: 13 AF XY: 0.00798 AC XY: 1063 AN XY: 133228

Gnomad AFR exome AF: 0.000770

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.00647 AC: 9447 AN: 1459024 Hom.: 61 Cov.: 35 AF XY: 0.00685 AC XY: 4968 AN XY: 725720

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.0340

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.00291

Gnomad4 NFE exome AF: 0.00564

Gnomad4 OTH exome AF: 0.00888

GnomAD4 genome AF: 0.00601 AC: 916 AN: 152350 Hom.: 8 Cov.: 32 AF XY: 0.00584 AC XY: 435 AN XY: 74496

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00912

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00689

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00726 Hom.: 9

Bravo AF: 0.00628

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 70/13004=0.53% -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 22995991, 20981092, 19464101, 24376681, 27884173, 27535533) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NKX2-5: BP4, BS1, BS2 -

Atrial septal defect 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Atrial septal defect Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 07, 2015

- -

Lissencephaly due to TUBA1A mutation Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous c.543G>A (p.Gln181=) variant in NKX2-5 has been identified in at least 2 individuals with cardiac disease (PMID: 19464101, 24376681) but has also been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for cardiac disease. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2015

This alteration is classified as likely 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	-0.45
Cadd	Benign	13
Dann	Benign	0.97

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: rs72554028; hg19: chr5-172660004;