rs137914723

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_014391.3(ANKRD1):c.348G>A(p.Thr116=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,564,118 control chromosomes in the GnomAD database, including 356 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 40 hom., cov: 29)

Exomes 𝑓: 0.0034 ( 316 hom. )

Consequence

ANKRD1
NM_014391.3 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.186

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 10-90918970-C-T is Benign according to our data. Variant chr10-90918970-C-T is described in ClinVar as [Benign]. Clinvar id is 45633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-90918970-C-T is described in Lovd as [Benign]. Variant chr10-90918970-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3 linkuse as main transcript	c.348G>A	p.Thr116=	splice_region_variant, synonymous_variant	4/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4 linkuse as main transcript	c.348G>A	p.Thr116=	splice_region_variant, synonymous_variant	4/9	1	NM_014391.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00771

AC:

1026

AN:

133122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0124

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000185

Gnomad OTH

AF:

0.0165

GnomAD3 exomes

AF:

0.0146

AC:

3526

AN:

240686

Hom.:

270

AF XY:

0.0108

AC XY:

1413

AN XY:

130932

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.0979

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0106

Gnomad SAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.00973

GnomAD4 exome

AF:

0.00342

AC:

4896

AN:

1430932

Hom.:

316

Cov.:

AF XY:

0.00286

AC XY:

2039

AN XY:

713034

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.0939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0141

Gnomad4 SAS exome

AF:

0.000293

Gnomad4 FIN exome

AF:

0.0000592

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00309

GnomAD4 genome

AF:

0.00775

AC:

1032

AN:

133186

Hom.:

Cov.:

AF XY:

0.00851

AC XY:

551

AN XY:

64736

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.0625

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0127

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000185

Gnomad4 OTH

AF:

0.0164

Alfa

AF:

0.00295

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00665

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2015	p.Thr116Thr in exon 4 of ANKRD1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 11.6% (1317/11318 ) of Latino chromosomes including 90 homozygotes and 1.3% (110/8288) of East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org/; dbSNP rs137914723). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2017	Variant summary: The ANKRD1 c.348G>A (p.Thr116Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant affects binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1468/117822 control chromosomes (91 homozygotes) from ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.116363 (1317/11318). This frequency is about 3385 times the estimated maximal expected allele frequency of a pathogenic ANKRD1 variant (0.0000344), thus this is a common benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign/likely benign. This variant was also reported as a polymorphism in the literature (Arimura _2009). Taken together, this variant is classified as benign. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 19, 2015

- -

ANKRD1-related dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.56

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over