rs759446749

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The ENST00000343849.3(CAV3):c.165C>A(p.Asp55Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,828 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D55G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CAV3
ENST00000343849.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.68

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 Uncertain_significance. Variant got 2 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 ENST00000343849.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

BS2

High AC in GnomAdExome4 at 8 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAV3	NM_033337.3 linkuse as main transcript	c.165C>A	p.Asp55Glu	missense_variant	2/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5 linkuse as main transcript	c.165C>A	p.Asp55Glu	missense_variant	2/3		NP_001225.1
OXTR	XR_007095681.1 linkuse as main transcript	n.1885-2974G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CAV3	ENST00000343849.3 linkuse as main transcript	c.165C>A	p.Asp55Glu	missense_variant	2/2	1	NM_033337.3	ENSP00000341940	P1
CAV3	ENST00000397368.2 linkuse as main transcript	c.165C>A	p.Asp55Glu	missense_variant	2/3	1		ENSP00000380525	P1
CAV3	ENST00000472766.1 linkuse as main transcript	n.155+11586C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251312

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135818

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Caveolinopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 20, 2021

The CAV3 c.165C>A (p.Asp55Glu) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.000009 in the European (Non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. The Asp55 residue is located in the scaffolding region of the caveolin domain (Fulizio et al. 2005). Based on the limited evidence, the p.Asp55Glu variant is classified as a variant of uncertain significance for caveolinopathies. -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CAV3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 55 of the CAV3 protein (p.Asp55Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.86

.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.15

T;T

Sift4G

Benign

0.098

T;T

Polyphen

0.93

P;P

Vest4

0.88

MutPred

0.85

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

1.0

MPC

1.4

ClinPred

0.93

GERP RS

0.39

Varity_R

0.50

gMVP

0.81

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