NM_003476.5:c.10T>C

Variant summary

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

The NM_003476.5(CSRP3):ā€‹c.10T>Cā€‹(p.Trp4Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,613,994 control chromosomes in the GnomAD database, including 17 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: š‘“ 0.0026 ( 1 hom., cov: 32)
Exomes š‘“: 0.0040 ( 16 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

6
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:16

Conservation

PhyloP100: 7.40
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]

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=0.009798527).
BP6
Variant 11-19192439-A-G is Benign according to our data. Variant chr11-19192439-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8776.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3, Likely_benign=8}. Variant chr11-19192439-A-G is described in Lovd as [Benign]. Variant chr11-19192439-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0026 (396/152286) while in subpopulation NFE AF= 0.00463 (315/68020). AF 95% confidence interval is 0.00421. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 16 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CSRP3NM_003476.5 linkc.10T>C p.Trp4Arg missense_variant Exon 2 of 6 ENST00000265968.9 NP_003467.1 P50461-1A2TDB8
CSRP3NM_001369404.1 linkc.10T>C p.Trp4Arg missense_variant Exon 2 of 5 NP_001356333.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CSRP3ENST00000265968.9 linkc.10T>C p.Trp4Arg missense_variant Exon 2 of 6 1 NM_003476.5 ENSP00000265968.3 P50461-1

Frequencies

GnomAD3 genomes
AF:
0.00260
AC:
396
AN:
152168
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000627
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.00137
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.000659
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00463
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00222
AC:
558
AN:
251372
Hom.:
1
AF XY:
0.00228
AC XY:
310
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.000925
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000751
Gnomad FIN exome
AF:
0.000462
Gnomad NFE exome
AF:
0.00418
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00404
AC:
5901
AN:
1461708
Hom.:
16
Cov.:
31
AF XY:
0.00394
AC XY:
2866
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.000961
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000765
Gnomad4 FIN exome
AF:
0.000842
Gnomad4 NFE exome
AF:
0.00500
Gnomad4 OTH exome
AF:
0.00275
GnomAD4 genome
AF:
0.00260
AC:
396
AN:
152286
Hom.:
1
Cov.:
32
AF XY:
0.00246
AC XY:
183
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.000625
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.000659
Gnomad4 NFE
AF:
0.00463
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00373
Hom.:
2
Bravo
AF:
0.00284
TwinsUK
AF:
0.00917
AC:
34
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00536
AC:
46
ExAC
AF:
0.00236
AC:
287
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00403
EpiControl
AF:
0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:16
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:5
-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 30, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 11, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The variant, CSRP3 c.10T>C (p.Trp4Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 280268 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 170 fold of the estimated maximal expected allele frequency for a pathogenic variant in CSRP3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In conflict with the population data, in vitro and in vivo functional studies showed that p.W4R completely disrupted T-cap binding, and a mouse model expressing p.W4R showed age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype (Knoll 2002, Knoll 2010). However, no human studies are available to date to confirm an effect in humans. Though this variant has been reported in the literature in several patients with either Hypertrophic- or Dilated Cardiomyopathy, it was also found in several controls, with a negative family history of heart disease (Geier 2008, Newman 2005). Moreover, the variant has been shown not to co-segregate with disease in multiple families (Geier 2008, Mohaptra 2003). Additionally, the variant has been reported to co-occur with multiple pathogenic/potentially pathogenic variants, including MYBPC3 F1113I, MYH7 T1377M, MYH7 I511T, MYBPC3 Q1233X and TNNT2 K210del (Bos 2006, Geier 2008, Mohaptra 2003), and it was noted that there was no correlation between the presence of the W4R variant and the severity / progression of the disease (Geier 2008). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x), likely benign (4x) or VUS (1x). Given the strong population and segregation studies data, this variant is likely not a disease-causing mutation in isolation, but functional studies indicate that it affects function and could act as a phenotypic modifier in cardiomyopathies. Taken together, this variant was classified as likely benign, until additional information is available. -

Apr 08, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

May 23, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:5
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 10, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CSRP3: BS2 -

Hypertrophic cardiomyopathy Uncertain:1Benign:1
-
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 06, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 12 Uncertain:1
-
Laboratory of Genetics and Molecular Cardiology, University of SĆ£o Paulo
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1M Uncertain:1
Sep 15, 2008
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Cardiomyopathy Uncertain:1
Sep 29, 2017
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

CSRP3-related disorder Benign:1
Sep 30, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Hypertrophic cardiomyopathy;C0520806:Sudden unexplained death Benign:1
Oct 10, 2018
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiovascular phenotype Benign:1
Aug 30, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Pathogenic
0.98
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.49
T;.;.;T;T;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D;.;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.0098
T;T;T;T;T;T
MetaSVM
Benign
-0.44
T
MutationAssessor
Uncertain
2.0
M;.;.;M;M;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.3
D;.;.;.;D;.
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D;.;.;.;D;.
Sift4G
Pathogenic
0.0
D;.;.;.;D;.
Polyphen
0.89
P;.;.;P;P;.
Vest4
0.74
MutPred
0.78
Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP
0.88
MPC
0.30
ClinPred
0.042
T
GERP RS
6.0
Varity_R
0.75
gMVP
0.54

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.

Other links and lift over

dbSNP: rs45550635; hg19: chr11-19213986; API