chr11-19210527-C-T

Variant names:

• chr11-19210527-C-T
• rs569978006
• ENST00000533783.2:c.-195G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000533783.2(CSRP3):​c.-195G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 137,440 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSRP3 ENST00000533783.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.86

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-AS1 (HGNC:54183): (CSRP3 and E2F8 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (209/137440) while in subpopulation NFE AF= 0.00228 (150/65844). AF 95% confidence interval is 0.00198. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3-AS1	NR_183675.1	n.207+13608C>T		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000533783.2	c.-195G>A		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000431813.1
CSRP3-AS1	ENST00000527978.1	n.145+13608C>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 209 AN: 137364 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00333

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000676

Gnomad FIN AF: 0.000144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00328

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 82 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00152 AC: 209 AN: 137440 Hom.: 1 Cov.: 27 AF XY: 0.00146 AC XY: 95 AN XY: 65168

Gnomad4 AFR AF: 0.000654

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000678

Gnomad4 FIN AF: 0.000144

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00324

Alfa AF: 0.0000531 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 12 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Jul 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.9
DANN	Benign	0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs569978006; hg19: chr11-19232074;