rs138218523

Positions:

chr11-19186331-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003476.5(CSRP3):c.299G>A(p.Arg100His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,156 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 3 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13

Conservation

PhyloP100: 2.76

Variant links:

Genes affected

CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

CSRP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010199755).

BP6

Variant 11-19186331-C-T is Benign according to our data. Variant chr11-19186331-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44694.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=2}. Variant chr11-19186331-C-T is described in Lovd as [Benign]. Variant chr11-19186331-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000906 (138/152274) while in subpopulation NFE AF= 0.00122 (83/68024). AF 95% confidence interval is 0.00101. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1 linkuse as main transcript	c.130G>A	p.Ala44Thr	missense_variant	3/5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.299G>A	p.Arg100His	missense_variant	4/6	1	NM_003476.5	ENSP00000265968	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00117

AC:

294

AN:

251360

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00504

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000755

AC:

1103

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000755

AC XY:

549

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00464

Gnomad4 NFE exome

AF:

0.000702

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152274

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000917

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.000273

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24082139, 19035361, 23861362, 30012424) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2012	Variant classified as Uncertain Significance - Favor Benign. The Arg100His varia nt (CSRP3) has been reported in 1 individual with HCM (Anderson 2009) and has be en detected in 1 individual with HCM tested by our laboratory who carried a path ogenic HCM variant (LMM unpublished data). This variant has been identified in 0.1% (6/7020) of European American chromosomes from a broad population by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs13821852 3). While this frequency suggests that it is more likely benign but it is too lo w to confidently rule out a disease causing role. Additional information is need ed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2021	- -

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -
Uncertain significance, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

Hypertrophic cardiomyopathy 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CSRP3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 04, 2018

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2019

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

Benign

0.092

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.23

M_CAP

Benign

0.015

MetaRNN

Benign

0.010

MutationTaster

Benign

1.0

D;D

ClinPred

0.038

GERP RS

5.8

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