rs72546668

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_033337.3(CAV3):c.233C>A(p.Thr78Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,790 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T78M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 3.78

Variant links:

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]

CAV3 links:

OXTR (HGNC:):

OXTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_033337.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-8745644-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAV3	NM_033337.3 linkuse as main transcript	c.233C>A	p.Thr78Lys	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5 linkuse as main transcript	c.233C>A	p.Thr78Lys	missense_variant	2/3
OXTR	XR_007095681.1 linkuse as main transcript	n.1885-3042G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CAV3	ENST00000343849.3 linkuse as main transcript	c.233C>A	p.Thr78Lys	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2 linkuse as main transcript	c.233C>A	p.Thr78Lys	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1 linkuse as main transcript	n.155+11654C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250926

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (CAV3)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Benign

0.12

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.9

N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.099

T;T

Sift4G

Benign

0.067

T;T

Polyphen

0.70

P;P

Vest4

0.63

MutPred

0.90

Gain of ubiquitination at T78 (P = 0.0247);Gain of ubiquitination at T78 (P = 0.0247);

MVP

0.99

MPC

0.91

ClinPred

0.75

GERP RS

4.6

Varity_R

0.84

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over