rs774726585

Variant names:

• chr5-173233518-AAT-A
• rs774726585
• NM_004387.4:c.335-311_335-310delAT

Your query was ambiguous. Multiple possible variants found:

• chr5-173233518-AAT-A
• chr5-173233518-AAT-AATAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004387.4(NKX2-5):​c.335-311_335-310delAT 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 19. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.335-311_335-310delAT		intron_variant	Intron 1 of 1	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.335-19_335-18delAT		intron_variant	Intron 1 of 1	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.335-56_335-55delAT		intron_variant	Intron 1 of 1	2		ENSP00000427906.1

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

GnomAD2 exomes AF: 0.0128 AC: 1210 AN: 94176 AF XY: 0.0128

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 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 AC: 470 AN: 9952

Gnomad4 AMR exome AF: 0.00720 AC: 165 AN: 22904

Gnomad4 ASJ exome AF: 0.0190 AC: 317 AN: 16710

Gnomad4 EAS exome AF: 0.00208 AC: 60 AN: 28826

Gnomad4 SAS exome AF: 0.0189 AC: 797 AN: 42266

Gnomad4 FIN exome AF: 0.0102 AC: 240 AN: 23628

Gnomad4 NFE exome AF: 0.00672 AC: 2530 AN: 376520

Gnomad4 Remaining exome AF: 0.0108 AC: 293 AN: 27136

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 AC: 0.00246305 AN: 0.00246305

Gnomad4 AMR AF: 0.00375 AC: 0.00375088 AN: 0.00375088

Gnomad4 ASJ AF: 0.0169 AC: 0.0168815 AN: 0.0168815

Gnomad4 EAS AF: 0.000207 AC: 0.000207383 AN: 0.000207383

Gnomad4 SAS AF: 0.0177 AC: 0.0176606 AN: 0.0176606

Gnomad4 FIN AF: 0.00147 AC: 0.00146893 AN: 0.00146893

Gnomad4 NFE AF: 0.00405 AC: 0.0040512 AN: 0.0040512

Gnomad4 OTH AF: 0.00315 AC: 0.00314795 AN: 0.00314795

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

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism (auto)

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;