rs142354133

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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. 2/2 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

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3 linkuse as main transcript	c.347C>T	p.Thr116Met	missense_variant, splice_region_variant	4/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4 linkuse as main transcript	c.347C>T	p.Thr116Met	missense_variant, splice_region_variant	4/9	1	NM_014391.3	P1

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

GnomAD3 exomes

AF:

0.000146

AC:

AN:

245818

Hom.:

AF XY:

0.000150

AC XY:

AN XY:

133362

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 SAS exome

AF:

0.0000657

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000900

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.000210

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.0000394

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.0000676

GnomAD4 genome

AF:

0.000183

AC:

AN:

131346

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

63712

show subpopulations

Gnomad4 AFR

AF:

0.000135

Gnomad4 AMR

AF:

0.000302

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000245

Gnomad4 FIN

AF:

0.000111

Gnomad4 NFE

AF:

0.000201

Gnomad4 OTH

AF:

0.000545

Alfa

AF:

0.000199

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 09, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2023

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

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

MutationTaster

Benign

1.0

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

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

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