rs751739709

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014391.3(ANKRD1):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,728 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ANKRD1
NM_014391.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.64

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/9	1	NM_014391.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250788

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135540

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:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460588

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Oct 11, 2017

This infant with asymmetric LV hypertrophy had genetic testing for hypertrophic cardiomyopathy with the Invitae laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: A2ML1, ABCC9, ACADVL, ACTC1, ACTN2, AGL, ALMS1, ANKRD1, BAG3, BRAF, CACNA1C, CALR3, CAV3, CBL, CHRM2, CPT2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GLA, HCN4, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MAP2K1, MAP2K2, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NF1, NKX2-5, NPPA, NRAS, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, PTPN11, RAF1, RASA1, RBM20, RIT1, RRAS, RYR2, SCN5A, SGCD, SHOC2, SLC22A5, SOS1, SOS2, SPRED1, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL The following genes were evaluated for sequence changes only: SDHA One variant was reported. p.Arg154Trp (c.460C>T) in exon 5 of the ANKRD1 gene (NM_014391.2) Chromosome location 10:92677581 G / A Based on the information reviewed below, we classify it as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The ANKRD1 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 2880) and hypertrophic cardiomyopathy (HCM) (PMID: 19608031). This specific variant has not been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. Arginine at this location is absolutely conserved across ~100 vertebrate species for which we have data. Nearby residues are also highly conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, although since this is a newly-characterized gene there are only 3 such variants listed total. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). It is present in gnomAD (a population database of 140,000 individuals not selected for cardiomyopathy) in 2 South Asian individuals, for an allele frequency in that ethnic group of 0.006%. Overall allele frequency among all ethnicities 0.0008%. There is also 1 non-Finnish European ancestry individual with a p.Arg154Gln variant. There is good sequencing coverage at this site. The gnomAD database includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. 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. The curators made an effort to exclude individuals with severe pediatric diseases. -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 154 of the ANKRD1 protein (p.Arg154Trp). This variant is present in population databases (rs751739709, gnomAD 0.006%). 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: 477609). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Jul 19, 2022

The p.R154W variant (also known as c.460C>T), located in coding exon 5 of the ANKRD1 gene, results from a C to T substitution at nucleotide position 460. The arginine at codon 154 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

1.0

Vest4

0.89

MVP

0.88

MPC

0.69

ClinPred

0.99

GERP RS

3.4

Varity_R

0.83

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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