rs142354133

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_014391.3(ANKRD1):c.347C>T(p.Thr116Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,567,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T116T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense, splice_region

Scores

Splicing: ADA: 0.9791

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.37

Publications

12 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 -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD1	NM_014391.3 link	c.347C>T	p.Thr116Met	missense_variant, splice_region_variant	Exon 4 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.347C>T	p.Thr116Met	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_014391.3	ENSP00000360762.3

Frequencies

GnomAD3 genomes

AF:

0.000183

AC:

AN:

131302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000303

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000245

Gnomad FIN

AF:

0.000111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000201

Gnomad OTH

AF:

0.000549

GnomAD2 exomes

AF:

0.000146

AC:

AN:

245818

AF XY:

0.000150

show subpopulations

Gnomad AFR exome

AF:

0.0000643

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

178

AN:

1436370

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

100

AN XY:

715500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31166

American (AMR)

AF:

0.0000900

AC:

AN:

44460

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25880

East Asian (EAS)

AF:

0.000210

AC:

AN:

38154

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85426

European-Finnish (FIN)

AF:

0.0000394

AC:

AN:

50774

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.000142

AC:

156

AN:

1095668

Other (OTH)

AF:

0.0000676

AC:

AN:

59174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000183

AC:

AN:

131346

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

63712

show subpopulations

African (AFR)

AF:

0.000135

AC:

AN:

29638

American (AMR)

AF:

0.000302

AC:

AN:

13232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

4442

South Asian (SAS)

AF:

0.000245

AC:

AN:

4076

European-Finnish (FIN)

AF:

0.000111

AC:

AN:

9042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000201

AC:

AN:

64546

Other (OTH)

AF:

0.000545

AC:

AN:

1836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000219

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23572067, 20497191, 19589340, 18273862, 19525294, 32880476) -

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Sep 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr116Met variant has been identified at low frequency in various populati ons by the Exome Aggregation Consortium (highest in Europeans; 14/65994 chromoso mes; ExAC, http://exac.broadinstitute.org/; dbSNP rs142354133). This variant has been reported in 1 adult with anomalous pulmonary venous return (TAPVR) and ASD (Cinquetti 2008) as well as 1 adult and one affected relative with DCM (Duboscq -Bidot 2009). In vitro functional studies provide some evidence that the p.Thr11 6Met variant may impact the protein (Cinquetti 2008, Duboscq-Bidot 2009), but th ese types of assays may not accurately represent biological function. In summary , the clinical significance of the p.Thr116Met variant is uncertain. -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 116 of the ANKRD1 protein (p.Thr116Met). This variant is present in population databases (rs142354133, gnomAD 0.03%). This missense change has been observed in individual(s) with total anomalous pulmonary venous return (TAPVR) and/or dilated cardiomyopathy (DCM) (PMID: 18273862, 19525294, 32880476). ClinVar contains an entry for this variant (Variation ID: 228439). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ANKRD1 function (PMID: 18273862, 19525294). 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

Sep 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T116M variant (also known as c.347C>T), located in coding exon 4 of the ANKRD1 gene, results from a C to T substitution at nucleotide position 347. The threonine at codon 116 is replaced by methionine, an amino acid with some similar properties, and is located in the PEST domain. In one study, this alteration was reported in a proband with total anomalous pulmonary venous return, and functional studies showed an increase in the stability of the protein; however the physiological relevance of this finding is unclear (Cinquetti R et al. Hum Mutat. 2008;29(4):468-74). This alteration was reported in a father and son with dilated cardiomyopathy (DCM) (Duboscq-Bidot L et al. Eur Heart J. 2009;30(17):2128-36), and has been reported in additional DCM cohorts (Verdonschot JAJ et al. Circ Genom Precis Med. 2020 10;13(5):476-487) as well as an exome sequencing cohort not selected for the presence of cardiovascular disease; however, details were limited (Norton N et al. Circ Cardiovasc Genet. 2012 Apr;5(2):167-74). This amino acid position is not well 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 variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.71

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

REVEL

Benign

0.26

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.77

Vest4

0.41

MVP

0.85

MPC

0.30

ClinPred

0.043

GERP RS

5.5

Varity_R

0.066

gMVP

0.35

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.75

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

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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