chr10-90915565-G-A

Position:

chr10-90915565-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014391.3(ANKRD1):c.827C>T(p.Ala276Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,613,884 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 30)

Exomes 𝑓: 0.0032 ( 18 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: 7.79

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011601299).

BP6

Variant 10-90915565-G-A is Benign according to our data. Variant chr10-90915565-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45639.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=7}. Variant chr10-90915565-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-90915565-G-A is described in Lovd as [Benign]. Variant chr10-90915565-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD1	NM_014391.3 linkuse as main transcript	c.827C>T	p.Ala276Val	missense_variant	8/9	ENST00000371697.4	NP_055206.2	Q15327A0A384NYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4 linkuse as main transcript	c.827C>T	p.Ala276Val	missense_variant	8/9	1	NM_014391.3	ENSP00000360762.3		Q15327

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

351

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00351

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00274

AC:

689

AN:

251052

Hom.:

AF XY:

0.00268

AC XY:

363

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00321

AC:

4690

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

2238

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00396

GnomAD4 genome

AF:

0.00231

AC:

351

AN:

152208

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.0204

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00351

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00370

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2018	The p.Ala276Val variant in ANKRD1 is classified as benign because it has been de tected in 2% (212/10136) of Ashkenazi Jewish chromosomes by gnomAD (http://gnoma d.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2018	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2015	- -

not provided

Benign:4

Likely 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.827C>T (p.Ala276Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). In vitro functional analysis shows that this variant leads to decrease in transcriptional repression activity (Duboscq-Bidot_2009).This variant was found in 346/121722 control chromosomes (1 homozygote) including ExAC at a frequency of 0.0028425, which is approximately 83 times the estimated maximal expected allele frequency of a pathogenic ANKRD1 variant (0.0000344), suggesting this variant is likely a benign polymorphism. This variant has been reported in two siblings with DCM without strong evidence for causality (Duboscq-Bidot_2009). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign/benign. Taken together, this variant is currently classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANKRD1: BP4, BS2 -

Congenital total pulmonary venous return anomaly

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 19, 2016	- -

Primary dilated cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy;C1135191:Systolic heart failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 01, 2019

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 30, 2019

- -

ANKRD1-related dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 23, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2017

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

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.026

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.41

Sift

Benign

0.044

Sift4G

Uncertain

0.038

Polyphen

0.61

Vest4

0.65

MVP

0.85

MPC

0.18

ClinPred

0.039

GERP RS

5.4

Varity_R

0.19

gMVP

0.79

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

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