11-19188286-A-T

Variant names:

• chr11-19188286-A-T
• NM_003476.5:c.131T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_003476.5(CSRP3):​c.131T>A​(p.Leu44His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. L44P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.22

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain LIM zinc-binding 1 (size 51) in uniprot entity CSRP3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003476.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-19188286-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.131T>A	p.Leu44His	missense_variant	Exon 3 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.113-1938T>A		intron_variant	Intron 2 of 4		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.131T>A	p.Leu44His	missense_variant	Exon 3 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;.;D;D
Vest4		0.94
MutPred		0.85		Loss of stability (P = 0.0118);Loss of stability (P = 0.0118);Loss of stability (P = 0.0118);Loss of stability (P = 0.0118);
MVP		0.99
MPC		0.43
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-19209833;