5-173233001-C-T

Variant names:

• chr5-173233001-C-T
• rs72554028
• NM_004387.4:c.543G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004387.4(NKX2-5):​c.543G>A​(p.Gln181Gln) 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:18
• Conservation: PhyloP100: 3.37
• Publications: 27 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
• 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)
• hypothyroidism, congenital, nongoitrous, 5

  Inheritance: Unknown, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 36658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 916 AD,SD,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	NM_004387.4	MANE Select	c.543G>A	p.Gln181Gln	synonymous	Exon 2 of 2	NP_004378.1	P52952-1
	NKX2-5	NM_001166176.2		c.*342G>A		3_prime_UTR	Exon 2 of 2	NP_001159648.1	P52952-2
	NKX2-5	NM_001166175.2		c.*496G>A		3_prime_UTR	Exon 2 of 2	NP_001159647.1	P52952-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.543G>A	p.Gln181Gln	synonymous	Exon 2 of 2	ENSP00000327758.4	P52952-1
	NKX2-5	ENST00000424406.2	TSL:1	c.*496G>A		3_prime_UTR	Exon 2 of 2	ENSP00000395378.2	P52952-3
	NKX2-5	ENST00000521848.1	TSL:2	c.*342G>A		3_prime_UTR	Exon 2 of 2	ENSP00000427906.1	P52952-2

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

GnomAD2 exomes AF: 0.00748 AC: 1836 AN: 245362 AF XY: 0.00798

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 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

African (AFR) AF: 0.00129 AC: 43 AN: 33438

American (AMR) AF: 0.00833 AC: 369 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 886 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0125 AC: 1073 AN: 86050

European-Finnish (FIN) AF: 0.00291 AC: 153 AN: 52644

Middle Eastern (MID) AF: 0.0216 AC: 119 AN: 5502

European-Non Finnish (NFE) AF: 0.00564 AC: 6269 AN: 1111120

Other (OTH) AF: 0.00888 AC: 535 AN: 60262

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

African (AFR) AF: 0.00108 AC: 45 AN: 41584

American (AMR) AF: 0.0113 AC: 173 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4822

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00689 AC: 469 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00616 Hom.: 9

Bravo AF: 0.00628

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	1	Atrial septal defect (1)
-	-	1	Atrial septal defect 7 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly due to TUBA1A mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		3.4
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs72554028; hg19: chr5-172660004;