10-90912882-C-G

Position:

chr10-90912882-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014391.3(ANKRD1):c.944G>C(p.Arg315Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.14

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1472323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3 linkuse as main transcript	c.944G>C	p.Arg315Pro	missense_variant	9/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4 linkuse as main transcript	c.944G>C	p.Arg315Pro	missense_variant	9/9	1	NM_014391.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250916

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 10, 2016

-p.Arg315Pro (R315P) (CGC>CCC): c.944 G>C in exon 9 of the ANKRD1 gene (NM_014391.2) Given the lack of case data and the presence of several variants occurring at a relatively high rate in control populations in the same codon, we consider this variant to be a variant of unknown significance, likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Testing other affected family members, if available, for the purposes of segregation analysis may assist with further interpretation. We have seen this variant in an individual with DCM. This variant did not segregate with disease in another family member with idiopathic LV dysfunction, though other non-genetic causes of LV dysfunction have not been ruled out as this time. The variant has not been reported in ClinVar or in the literature (as of 1/10/16). Codon 315 is the second to last codon of the protein. The laboratory report notes that in silico analysis with SIFT and PolyPhen-2 predict the variant to be neutral, but Mutation Taster predicts it to be deleterious. The Arginine at codon 315 is conserved among mammals. Neighboring amino acids are conserved in primates, but not in the cat or mouse. An allelic variant p.Arg315His has been reported in ClinVar by GeneDx and interpreted as a variant of unknown significance. No pathogenic variants have been reported at nearby codons. The nearest likely pathogenic variant reported in ClinVar is at residue 287. Although this particular amino acid substitution is not listed, there is variation at codon 315 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 1/10/2016). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Specifically, a total of 3 other missense variants have been observed in codon 315, two allelic variants at the second position of the codon (10: 92672639) and one variant at the next base in the third position of the codon (10: 92672640). Therefore, 1 in 6,070 individuals have missense variation at codon 315. The allelic variant p.Arg315His was observed in 7 of 60,204 individuals (6 of 5,789 people of Latino ancestry and 1 person of non-Finnish European ancestry). Another allelic p.Arg315Leu variant was observed in 2 of 60,204 individuals (2 of 33,369 people of non-Finnish European ancestry). Both of these variants were predicted to be benign and tolerated by Polyphen and SIFT, respectively. A third variant affecting same codon p.Arg315Leu was observed in 2 of 60,204 individuals (2 of 33,369 people of non-Finnish European ancestry). This variant was predicted to be possibly damaging by Polyphen and deleterious by SIFT. -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 315 of the ANKRD1 protein (p.Arg315Pro). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ANKRD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 518679). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.944G>C (p.R315P) alteration is located in exon 9 (coding exon 9) of the ANKRD1 gene. This alteration results from a G to C substitution at nucleotide position 944, causing the arginine (R) at amino acid position 315 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

Eigen

Benign

-0.14

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.68

M_CAP

Benign

0.014

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.20

MutationTaster

Benign

0.97

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.72

REVEL

Benign

0.12

Sift

Benign

0.079

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.14

MutPred

0.46

Loss of MoRF binding (P = 0.0023);

MVP

0.86

MPC

0.23

ClinPred

0.48

GERP RS

4.7

Varity_R

0.20

gMVP

0.80

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