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GeneBe

10-90912882-C-A

Variant summary

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

The NM_014391.3(ANKRD1):c.944G>T(p.Arg315Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,542 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: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

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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=0.20537275).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANKRD1NM_014391.3 linkuse as main transcriptc.944G>T p.Arg315Leu missense_variant 9/9 ENST00000371697.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANKRD1ENST00000371697.4 linkuse as main transcriptc.944G>T p.Arg315Leu missense_variant 9/91 NM_014391.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250916
Hom.:
0
AF XY:
0.00000737
AC XY:
1
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:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461542
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ANKRD1-related dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMay 18, 2018This sequence change replaces arginine with leucine at codon 315 of the ANKRD1 protein (p.Arg315Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs746392266, ExAC 0.003%). This variant has not been reported in the literature in individuals with ANKRD1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
0.0070
T
BayesDel_noAF
Benign
-0.23
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.090
T
Eigen
Benign
0.021
Eigen_PC
Benign
0.19
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
0.97
D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.98
N
REVEL
Benign
0.22
Sift
Uncertain
0.015
D
Sift4G
Benign
0.13
T
Polyphen
0.45
B
Vest4
0.25
MutPred
0.51
Loss of MoRF binding (P = 0.0121);
MVP
0.84
MPC
0.30
ClinPred
0.49
T
GERP RS
4.7
Varity_R
0.13
gMVP
0.76

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.

Other links and lift over

dbSNP: rs746392266; hg19: chr10-92672639; API