rs141376679

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014391.3(ANKRD1):c.234A>T(p.Arg78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,608,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.33

Publications

1 publications found

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 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

ANKRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3 link	c.234A>T	p.Arg78Ser	missense_variant	Exon 3 of 9	ENST00000371697.4	NP_055206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4 link	c.234A>T	p.Arg78Ser	missense_variant	Exon 3 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000114

AC:

AN:

244958

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000995

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1456320

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

724506

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33212

American (AMR)

AF:

0.000384

AC:

AN:

44302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

85598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000231

AC:

257

AN:

1110180

Other (OTH)

AF:

0.000116

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41546

American (AMR)

AF:

0.000392

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with DCM in the published literature (PMID: 32880476); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32880476) -

Oct 27, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Apr 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg78Ser variant in ANKRD1 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8598 of European American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14 1376679). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. Additional information is needed to fully asse ss the clinical significance of the Arg78Ser variant. -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 78 of the ANKRD1 protein (p.Arg78Ser). This variant is present in population databases (rs141376679, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 162750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANKRD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Mar 31, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R78S variant (also known as c.234A>T), located in coding exon 3 of the ANKRD1 gene, results from an A to T substitution at nucleotide position 234. The arginine at codon 78 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

0.17

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.79

MutationAssessor

Pathogenic

2.9

PhyloP100

1.3

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.43

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.61

MutPred

0.37

Gain of phosphorylation at R78 (P = 0.0102);

MVP

0.86

MPC

0.41

ClinPred

0.73

GERP RS

3.5

Varity_R

0.49

gMVP

0.50

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over