rs796052171

chr3-8733913-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_033337.3(CAV3):c.37A>T(p.Ile13Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I13V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.30

Genes affected

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

SSUH2 (HGNC:24809): (ssu-2 homolog) Involved in odontogenesis. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 61 pathogenic changes around while only 13 benign (82%) in NM_033337.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-8733913-A-T is Pathogenic according to our data. Variant chr3-8733913-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207882.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.37A>T	p.Ile13Phe	missense_variant	1/2	ENST00000343849.3
CAV3	NM_001234.5	c.37A>T	p.Ile13Phe	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.37A>T	p.Ile13Phe	missense_variant	1/2	1	NM_033337.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Long QT syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Medical Research Institute, Tokyo Medical and Dental University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Benign	0.92	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.52	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.73	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0030	B;B
Vest4		0.74
MutPred		0.52		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		1.0
MPC		0.84
ClinPred		0.52	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.84

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: rs796052171; hg19: chr3-8775599;