NM_014391.3:c.*59A>G

Variant names:

• chr10-90912807-T-C
• rs3939
• NM_014391.3:c.*59A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014391.3(ANKRD1):​c.*59A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,458,726 control chromosomes in the GnomAD database, including 161,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12678 hom., cov: 32)
  • Exomes 𝑓: 0.47 (149293 hom.)
• Consequence: ANKRD1 NM_014391.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.638
• Publications: 18 publications found

Genes affected

ANKRD1 (HGNC:15819): (ankyrin repeat domain 1) The protein encoded by this gene is localized to the nucleus of endothelial cells and is induced by IL-1 and TNF-alpha stimulation. Studies in rat cardiomyocytes suggest that this gene functions as a transcription factor. Interactions between this protein and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system. [provided by RefSeq, Jul 2008]

ANKRD1 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-90912807-T-C is Benign according to our data. Variant chr10-90912807-T-C is described in ClinVar as Benign. ClinVar VariationId is 301603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3	c.*59A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4	c.*59A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59725 AN: 152034 Hom.: 12682 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.473 AC: 617617 AN: 1306574 Hom.: 149293 Cov.: 18 AF XY: 0.471 AC XY: 309912 AN XY: 658412

African (AFR) AF: 0.195 AC: 5912 AN: 30380

American (AMR) AF: 0.490 AC: 21792 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 11907 AN: 25112

East Asian (EAS) AF: 0.360 AC: 14019 AN: 38920

South Asian (SAS) AF: 0.402 AC: 33327 AN: 82926

European-Finnish (FIN) AF: 0.461 AC: 24472 AN: 53082

Middle Eastern (MID) AF: 0.439 AC: 2407 AN: 5482

European-Non Finnish (NFE) AF: 0.493 AC: 478552 AN: 970962

Other (OTH) AF: 0.457 AC: 25229 AN: 55216

GnomAD4 genome AF: 0.393 AC: 59732 AN: 152152 Hom.: 12678 Cov.: 32 AF XY: 0.393 AC XY: 29246 AN XY: 74384

African (AFR) AF: 0.209 AC: 8658 AN: 41524

American (AMR) AF: 0.463 AC: 7083 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1599 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1885 AN: 5188

South Asian (SAS) AF: 0.409 AC: 1971 AN: 4824

European-Finnish (FIN) AF: 0.454 AC: 4802 AN: 10578

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32248 AN: 67954

Other (OTH) AF: 0.414 AC: 873 AN: 2110

Alfa AF: 0.454 Hom.: 25695

Bravo AF: 0.385

Asia WGS AF: 0.371 AC: 1294 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary dilated cardiomyopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.63
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs3939; hg19: chr10-92672564; COSMIC: COSV65467427; COSMIC: COSV65467427;