11-19188281-T-C

Variant names:

• chr11-19188281-T-C
• rs137852765
• NM_003476.5:c.136A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_003476.5(CSRP3):​c.136A>G​(p.Ser46Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93
• Publications: 0 publications found

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: SD, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• hypertrophic cardiomyopathy 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1M

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_003476.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• BS2: High AC in GnomAdExome4 at 6 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003476.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	NM_003476.5	MANE Select	c.136A>G	p.Ser46Gly	missense	Exon 3 of 6	NP_003467.1	A2TDB8
	CSRP3	NM_001369404.1		c.113-1933A>G		intron	N/A	NP_001356333.1	A0A3B3ISZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	ENST00000265968.9	TSL:1 MANE Select	c.136A>G	p.Ser46Gly	missense	Exon 3 of 6	ENSP00000265968.3	P50461-1
	CSRP3	ENST00000533783.2	TSL:1	c.136A>G	p.Ser46Gly	missense	Exon 4 of 7	ENSP00000431813.1	P50461-1
	CSRP3	ENST00000951070.1		c.145A>G	p.Ser49Gly	missense	Exon 3 of 6	ENSP00000621129.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460302 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726450

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4476

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.61		Loss of glycosylation at S46 (P = 0.0123)
MVP		0.96
MPC		0.36
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.24
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852765; hg19: chr11-19209828;