5-173233518-AAT-A

Position:

• chr5-173233518-AAT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004387.4(NKX2-5):​c.335-311_335-310del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 687,762 control chromosomes in the GnomAD database, including 96 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 19)
  • Exomes 𝑓: 0.0089 (92 hom.)
• Consequence: NKX2-5 NM_004387.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.455

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 -16 ACMG points.

• BP6: Variant 5-173233518-AAT-A is Benign according to our data. Variant chr5-173233518-AAT-A is described in ClinVar as [Likely_benign]. Clinvar id is 445633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173233518-AAT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00408 (561/137630) while in subpopulation SAS AF= 0.0177 (77/4360). AF 95% confidence interval is 0.0145. There are 4 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.335-311_335-310del		intron_variant		ENST00000329198.5	NP_004378.1
NKX2-5	XM_017009071.3	c.*526_*527del		3_prime_UTR_variant	2/2		XP_016864560.1
NKX2-5	NM_001166175.2	c.335-19_335-18del		intron_variant			NP_001159647.1
NKX2-5	NM_001166176.2	c.335-56_335-55del		intron_variant			NP_001159648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.335-311_335-310del		intron_variant		1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.335-19_335-18del		intron_variant		1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.335-56_335-55del		intron_variant		2		ENSP00000427906

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 561 AN: 137564 Hom.: 4 Cov.: 19

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00801

Gnomad AMR AF: 0.00376

Gnomad ASJ AF: 0.0169

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.0181

Gnomad FIN AF: 0.00147

Gnomad MID AF: 0.0140

Gnomad NFE AF: 0.00405

Gnomad OTH AF: 0.00317

GnomAD3 exomes AF: 0.0128 AC: 1210 AN: 94176 Hom.: 50 AF XY: 0.0128 AC XY: 667 AN XY: 52246

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.00913

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00322

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.00890 AC: 4898 AN: 550132 Hom.: 92 AF XY: 0.00915 AC XY: 2644 AN XY: 288838

Gnomad4 AFR exome AF: 0.0472

Gnomad4 AMR exome AF: 0.00720

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.00208

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00408 AC: 561 AN: 137630 Hom.: 4 Cov.: 19 AF XY: 0.00398 AC XY: 267 AN XY: 67146

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.00375

Gnomad4 ASJ AF: 0.0169

Gnomad4 EAS AF: 0.000207

Gnomad4 SAS AF: 0.0177

Gnomad4 FIN AF: 0.00147

Gnomad4 NFE AF: 0.00405

Gnomad4 OTH AF: 0.00315

Alfa AF: 0.00228 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774726585; hg19: chr5-172660521;