11-19182041-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003476.5(CSRP3):c.*629T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 152,830 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (477 hom., cov: 32)
  • Exomes 𝑓: 0.064 (1 hom.)
• Consequence: CSRP3 NM_003476.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-19182041-A-G is Benign according to our data. Variant chr11-19182041-A-G is described in ClinVar as [Benign]. Clinvar id is 303945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.*629T>C		3_prime_UTR_variant	6/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.*592T>C		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.*629T>C		3_prime_UTR_variant	6/6	1	NM_003476.5	P1
CSRP3	ENST00000533783.2	c.*629T>C		3_prime_UTR_variant	7/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.0678 AC: 10322 AN: 152210 Hom.: 477 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.0748

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.0903

GnomAD4 exome AF: 0.0637 AC: 32 AN: 502 Hom.: 1 Cov.: 0 AF XY: 0.0612 AC XY: 17 AN XY: 278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0366

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0746

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.0677 AC: 10317 AN: 152328 Hom.: 477 Cov.: 32 AF XY: 0.0689 AC XY: 5132 AN XY: 74488

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.0748

Gnomad4 ASJ AF: 0.0847

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.0389

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.0888

Alfa AF: 0.0793 Hom.: 207

Bravo AF: 0.0626

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	8.6
Dann	Benign	0.52

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: rs45599440; hg19: chr11-19203588;