rs727504905

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_003476.5(CSRP3):c.334G>C(p.Ala112Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A112E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CSRP3
NM_003476.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.03

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD, SD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
hypertrophic cardiomyopathy 12
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1M
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CSRP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11344808).

BP6

Variant 11-19186296-C-G is Benign according to our data. Variant chr11-19186296-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179500.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5 link	c.334G>C	p.Ala112Pro	missense_variant	Exon 4 of 6	ENST00000265968.9	NP_003467.1	P50461-1A2TDB8
CSRP3	NM_001369404.1 link	c.165G>C	p.Leu55Leu	synonymous_variant	Exon 3 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 link	c.334G>C	p.Ala112Pro	missense_variant	Exon 4 of 6	1	NM_003476.5	ENSP00000265968.3		P50461-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Feb 04, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A112P variant (also known as c.334G>C), located in coding exon 3 of the CSRP3 gene, results from a G to C substitution at nucleotide position 334. The alanine at codon 112 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jan 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala112Pro in exon 4 of CSRP3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, opposum, tasmanian devil, platypus, and wallaby have a proline (Pro) at this position despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of impac t to the protein. Ala112Pro in exon 4 of CSRP3 (allele frequency = n/a) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.75

.;.;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.060

N;N;N

PhyloP100

2.0

PrimateAI

Benign

0.46

PROVEAN

Benign

0.080

N;.;N

REVEL

Benign

0.073

Sift

Benign

0.36

T;.;T

Sift4G

Benign

0.31

T;.;T

Polyphen

0.0

B;B;B

Vest4

0.18

MutPred

0.37

Loss of MoRF binding (P = 0.0837);Loss of MoRF binding (P = 0.0837);Loss of MoRF binding (P = 0.0837);

MVP

0.61

MPC

0.078

ClinPred

0.086

GERP RS

3.9

Varity_R

0.086

gMVP

0.46

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over