rs116840798

chr3-8745598-A-Cchr3-8745598-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_033337.3(CAV3):c.187A>C(p.Thr63Pro) 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. 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. T63I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87

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]

OXTR (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.187A>C	p.Thr63Pro	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.187A>C	p.Thr63Pro	missense_variant	2/3
OXTR	XR_007095681.1	n.1885-2996T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.187A>C	p.Thr63Pro	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.187A>C	p.Thr63Pro	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11608A>C		intron_variant, non_coding_transcript_variant		2

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	0.79
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.98	D;D
Vest4		0.69
MutPred		0.67		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs116840798; hg19: chr3-8787284;