17-39666063-G-A

Position:

chr17-39666063-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003673.4(TCAP):c.458G>A(p.Arg153His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,603,976 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R153R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:2

Conservation

PhyloP100: 0.275

Variant links:

Genes affected

TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

TCAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014382958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	2/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	2/2	1	NM_003673.4	ENSP00000312624	P1
TCAP	ENST00000578283.1 linkuse as main transcript	c.386G>A	p.Arg129His	missense_variant	3/3	5		ENSP00000462787

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000210

AC:

AN:

242878

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

132260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.0000887

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000202

AC:

293

AN:

1451644

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

148

AN XY:

722566

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00235

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000589

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 07, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg153His (R153H; c.458G>A) in exon 2 of the TCAP gene (NM_003673.3). The Arg153His variant in TCAP has been previously identified in a Japanese male with HCM as well as in his affected sister (Hayashi 2004). Hayashi et al. also identified Arg153His in the proband's two sons who were asymptomatic at the time of evaluation. The Laboratory for Molecular Medicine at Harvard has reported in ClinVar that they have seen the varint in one Bangledeshi infant with RCM who carried a second variant in an HCM-associated gene. Functional studies in yeast have shown that the Arg153His variant leads to an increase in the ability of TCAP to bind with titin and CS-1 (Hayashi 2004). However, this in vitro assay may not accurately represent biological function. This is a conservative amino acid change, resulting in the replacement of a basic Arginine with a basic Histidine at a location that is poorly conserved across mammalian and vertebrate species. Of note, Histidine is the default amino acid in at least 8 species of mammal, suggesting that this change may be tolerated. Also, no mutations in nearby residues have been reported in association with cardiomyopathy, according to the lab report. According to ExAC, in silico analysis with SIFT or PolyPhen-2 predicts the variant to be tolerated/benign. In total the variant has been seen in 20/60,000 individuals from publicly available population datasets. The variant was not observed in published controls: It was absent from 240 Japanese and 70 Korean control individuals (Hayashi et al. 2004). The variant was detected in 2/8592 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs149585781) which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Our patient’s ancestry is African-American. Ancestry-matched individuals can be found in even greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5049 African-ancestry individuals. There are 20 individuals in ExAc with this variant and, of these, 17 of them are Caucasian, none of them are African, 2 are East Asian, and 1 is “Other”; this variant is most common in the Finnish population in ExAC with an allele frequency of 0.2%. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 14, 2014	The Arg153His variant in TCAP has been previously identified in an Asian individ ual with HCM as well as in one affected relative (Hayashi 2004). It has now been identified by our laboratory in one Bangledeshi infant with RCM carrying a seco nd variant in an HCM associated gene. The variant was detected in 2/8592 Europea n American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs149585781). Functional studies in yeast have shown that the Arg153His variant leads to an increase in the ability of TCAP to bind with titin and CS-1 (Hayashi 2004). However, this in vitro assay may not accurately r epresent biological function. However, arginine (Arg) at position 153 is not con served in evolution and 7 mammals carry the variant amino acid (gorilla, horse, white rhinoceros, shrew, elephant, manatee, wallaby, and platypus), suggesting t hat this change may be tolerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg153H is variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the available information is conf licting and additional information is needed to fully assess the clinical signif icance of the Arg153His variant. -

Hypertrophic cardiomyopathy 25

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 07, 2004

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2018

The R153H variant of uncertain significance has been identified in the TCAP gene. The variant has previously been reported in association with HCM and DCM (Hayashi et al., 2004; Akinrinade et al., 2015). Hayashi et al. (2004) identified R153H in a Japanese patient with HCM and his affected sister. The variant was also identified in the proband's two sons, who were asymptomatic at the time of evaluation (Hayashi et al., 2004). Akinrinade et al. (2015) identified R153H in a Finnish patient with DCM. Although the R153H variant was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, it was observed in 13/6,592 (~0.2%) alleles from individuals of European (Finnish) background in Exome Aggregation Consortium (ExAC). In addition, the R153H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and Histidine is the wild-type amino acid at this position in multiple species. Furthermore, 2/3 in silico algorithms predict this variant likely does not alter the protein structure/function. -

Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2018

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. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Uncertain

0.42

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.9

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.82

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.17

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;.

Vest4

0.050

MVP

0.90

MPC

0.33

ClinPred

0.033

GERP RS

-0.84

Varity_R

0.043

gMVP

0.29

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.

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