5-173233518-AAT-A

Variant names:

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

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
• Publications: 1 publications found

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]

NKX2-5 Gene-Disease associations (from GenCC):

• atrial septal defect 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• hypothyroidism, congenital, nongoitrous, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• NKX2.5-related congenital, conduction and myopathic heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tetralogy of fallot

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• conotruncal heart malformations

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated congenital asplenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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 VariationId is 445633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 passed quality control check.
• BS2: High AC in GnomAd4 at 561 AD,Unknown,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004387.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	NM_004387.4	MANE Select	c.335-311_335-310delAT		intron	N/A	NP_004378.1
	NKX2-5	NM_001166176.2		c.335-56_335-55delAT		intron	N/A	NP_001159648.1
	NKX2-5	NM_001166175.2		c.335-19_335-18delAT		intron	N/A	NP_001159647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.335-311_335-310delAT		intron	N/A	ENSP00000327758.4
	NKX2-5	ENST00000424406.2	TSL:1	c.335-19_335-18delAT		intron	N/A	ENSP00000395378.2
	NKX2-5	ENST00000521848.1	TSL:2	c.335-56_335-55delAT		intron	N/A	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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0472 AC: 470 AN: 9952

American (AMR) AF: 0.00720 AC: 165 AN: 22904

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 317 AN: 16710

East Asian (EAS) AF: 0.00208 AC: 60 AN: 28826

South Asian (SAS) AF: 0.0189 AC: 797 AN: 42266

European-Finnish (FIN) AF: 0.0102 AC: 240 AN: 23628

Middle Eastern (MID) AF: 0.0119 AC: 26 AN: 2190

European-Non Finnish (NFE) AF: 0.00672 AC: 2530 AN: 376520

Other (OTH) AF: 0.0108 AC: 293 AN: 27136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00246 AC: 88 AN: 35728

American (AMR) AF: 0.00375 AC: 53 AN: 14130

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 55 AN: 3258

East Asian (EAS) AF: 0.000207 AC: 1 AN: 4822

South Asian (SAS) AF: 0.0177 AC: 77 AN: 4360

European-Finnish (FIN) AF: 0.00147 AC: 13 AN: 8850

Middle Eastern (MID) AF: 0.0152 AC: 4 AN: 264

European-Non Finnish (NFE) AF: 0.00405 AC: 257 AN: 63438

Other (OTH) AF: 0.00315 AC: 6 AN: 1906

Alfa AF: 0.00228 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
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

Other links and lift over

dbSNP: rs774726585; hg19: chr5-172660521;