10-90918869-T-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_014391.3(ANKRD1):​c.449A>T​(p.Asp150Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000528 in 1,608,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D150G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

8
9
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 7.12

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3
MetaRNN computational evidence supports a deleterious effect, 0.82
BP6
Variant 10-90918869-T-A is Benign according to our data. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673. Variant chr10-90918869-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201673.
BS2
High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD1NM_014391.3 linkc.449A>T p.Asp150Val missense_variant Exon 4 of 9 ENST00000371697.4 NP_055206.2 Q15327A0A384NYH5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD1ENST00000371697.4 linkc.449A>T p.Asp150Val missense_variant Exon 4 of 9 1 NM_014391.3 ENSP00000360762.3 Q15327

Frequencies

GnomAD3 genomes
AF:
0.000303
AC:
46
AN:
151800
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00112
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000719
AC:
18
AN:
250284
AF XY:
0.0000591
show subpopulations
Gnomad AFR exome
AF:
0.00105
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000268
AC:
39
AN:
1456794
Hom.:
0
Cov.:
31
AF XY:
0.0000207
AC XY:
15
AN XY:
725092
show subpopulations
African (AFR)
AF:
0.000963
AC:
32
AN:
33226
American (AMR)
AF:
0.0000671
AC:
3
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39598
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86154
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52208
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1108798
Other (OTH)
AF:
0.0000498
AC:
3
AN:
60236
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.592
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000303
AC:
46
AN:
151800
Hom.:
0
Cov.:
30
AF XY:
0.000351
AC XY:
26
AN XY:
74140
show subpopulations
African (AFR)
AF:
0.00112
AC:
46
AN:
41200
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4806
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10550
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.564
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000199
Hom.:
0
Bravo
AF:
0.000321
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 07, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in a patient with DCM and a patient with elevated HDL-C in published literature (PMID: 35460704, 31983221); 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: 31983221, 35460704) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Uncertain:1
Apr 20, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Asp150Val variant in ANKRD1 has not been previously reported in individual s with cardiomyopathy, but has been identified in 0.1% (23/23930) of African chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org/; dbSNP rs150266349). This variant has been reported in ClinVar (Variation ID 201673) as of uncertain significance. Computational prediction tools and con servation analysis suggest that the p.Asp150Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp150Val variant is uncertain. -

ANKRD1-related dilated cardiomyopathy Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Aug 31, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely 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
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.020
T
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Uncertain
0.035
D
MutationAssessor
Uncertain
2.8
M
PhyloP100
7.1
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-8.0
D
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MVP
0.85
MPC
0.80
ClinPred
0.70
D
GERP RS
4.2
Varity_R
0.93
gMVP
0.81
Mutation Taster
=34/66
disease causing

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

Other links and lift over

dbSNP: rs150266349; hg19: chr10-92678626; API