NM_003476.5:c.*12G>A

Variant names:

• chr11-19182658-C-T
• rs45607943
• NM_003476.5:c.*12G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_003476.5(CSRP3):​c.*12G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,612,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: CSRP3 NM_003476.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -2.39

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006032467).
• BP6: Variant 11-19182658-C-T is Benign according to our data. Variant chr11-19182658-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-19182658-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.001 (153/152240) while in subpopulation AFR AF= 0.00342 (142/41546). AF 95% confidence interval is 0.00296. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.*12G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.428G>A	p.Arg143His	missense_variant	Exon 5 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968	c.*12G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251482 Hom.: 1 AF XY: 0.000258 AC XY: 35 AN XY: 135912

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000166 AC: 243 AN: 1460734 Hom.: 1 Cov.: 30 AF XY: 0.000154 AC XY: 112 AN XY: 726856

Gnomad4 AFR exome AF: 0.00401

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74422

Gnomad4 AFR AF: 0.00342

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.00115

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000420 AC: 51

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Aug 31, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CSRP3 c.*12G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00037 in 251482 control chromosomes, predominantly at a frequency of 0.0031 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 124 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 African or African-American origin. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 04, 2016

GeneDx

Significance: 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. -

Jan 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 23, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Benign:1

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.042
DANN	Benign	0.65
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0060	T;T
GERP RS		-11

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

Other links and lift over

dbSNP: rs45607943; hg19: chr11-19204205;