11-19188265-G-A

Variant names:

• chr11-19188265-G-A
• rs397516853
• NM_003476.5:c.152C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003476.5(CSRP3):​c.152C>T​(p.Ala51Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A51D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.85
• Publications: 3 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: 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_003476.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3239961).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	NM_003476.5	MANE Select	c.152C>T	p.Ala51Val	missense	Exon 3 of 6	NP_003467.1
	CSRP3	NM_001369404.1		c.113-1917C>T		intron	N/A	NP_001356333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	ENST00000265968.9	TSL:1 MANE Select	c.152C>T	p.Ala51Val	missense	Exon 3 of 6	ENSP00000265968.3
	CSRP3	ENST00000533783.2	TSL:1	c.152C>T	p.Ala51Val	missense	Exon 4 of 7	ENSP00000431813.1
	CSRP3	ENST00000649235.1		c.152C>T	p.Ala51Val	missense	Exon 4 of 7	ENSP00000497388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251060 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460612 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726616

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000447 AC: 2 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: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-0.35	N
PhyloP100		6.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.43
Sift	Benign	0.31	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.70
MutPred		0.43		Gain of sheet (P = 0.0477)
MVP		0.92
MPC		0.35
ClinPred		0.36	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.32
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs397516853; hg19: chr11-19209812;