rs148189486

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.313C>T(p.Pro105Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,612,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P105L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.55

Publications

14 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 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3 link	c.313C>T	p.Pro105Ser	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.313C>T	p.Pro105Ser	missense_variant	Exon 3 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes

AF:

0.000344

AC:

AN:

151194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000618

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000156

AC:

AN:

250210

AF XY:

0.000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000346

AC:

506

AN:

1460932

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

225

AN XY:

726756

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33402

American (AMR)

AF:

0.0000447

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000429

AC:

477

AN:

1111534

Other (OTH)

AF:

0.000398

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

107

134

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:

0.000344

AC:

AN:

151194

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.000171

AC:

AN:

41052

American (AMR)

AF:

0.000197

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000618

AC:

AN:

67914

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000332

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with cardiomyopathy in individuals in published literature (Moulik et al., 2009); Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 23299917, 19608030, 26187847, 27896284, 28672880, 30659708, 34426522, 30847666, 23861362) -

Primary dilated cardiomyopathy

Uncertain:1Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the ANKRD1 protein (p.Pro105Ser). This variant is present in population databases (rs148189486, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ANKRD1-related conditions (PMID: 19608030, 30847666). ClinVar contains an entry for this variant (Variation ID: 192112). 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%. Experimental studies have shown that this missense change affects ANKRD1 function (PMID: 19608030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P105S variant (also known as c.313C>T), located in coding exon 3 of the ANKRD1 gene, results from a C to T substitution at nucleotide position 313. The proline at codon 105 is replaced by serine, an amino acid with similar properties. This alteration was described in individuals with dilated cardiomyopathy but no segregation information was available (Moulik M et al. J. Am. Coll. Cardiol., 2009 Jul;54:325-33). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This alteration was reported to disrupt Talin-1 binding in a yeast two hybrid system. In addition, the same study also found that during mechanical stretch, this alteration would decrease P53 expression while increasing myogenin expression (Moulik M et al. J. Am. Coll. Cardiol., 2009 Jul;54:325-33). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in another 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

Benign

0.13

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Benign

0.031

Eigen_PC

Benign

0.094

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.70

M_CAP

Benign

0.033

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.5

PhyloP100

2.5

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.37

Sift

Uncertain

0.010

Sift4G

Benign

0.15

Polyphen

0.92

Vest4

0.28

MVP

0.82

MPC

0.25

ClinPred

0.15

GERP RS

4.6

Varity_R

0.17

gMVP

0.23

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -32

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