3-8733975-C-T

Position:

chr3-8733975-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_033337.3(CAV3):c.99C>T(p.Asn33Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,601,170 control chromosomes in the GnomAD database, including 60,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10596 hom., cov: 30)

Exomes 𝑓: 0.25 ( 49671 hom. )

Consequence

CAV3
NM_033337.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: -0.522

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:

SSUH2 (HGNC:):

SSUH2 links:

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

SSUH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 3-8733975-C-T is Benign according to our data. Variant chr3-8733975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 31709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-8733975-C-T is described in Lovd as [Benign]. Variant chr3-8733975-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.522 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV3	NM_033337.3 linkuse as main transcript	c.99C>T	p.Asn33Asn	synonymous_variant	1/2	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 linkuse as main transcript	c.99C>T	p.Asn33Asn	synonymous_variant	1/3		NP_001225.1	P56539

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3 linkuse as main transcript	c.99C>T	p.Asn33Asn	synonymous_variant	1/2	1	NM_033337.3	ENSP00000341940.2		P56539

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53036

AN:

151520

Hom.:

10583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.330

GnomAD3 exomes

AF:

0.294

AC:

73767

AN:

250794

Hom.:

11802

AF XY:

0.284

AC XY:

38572

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.323

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.397

Gnomad SAS exome

AF:

0.208

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.253

AC:

366328

AN:

1449532

Hom.:

49671

Cov.:

AF XY:

0.251

AC XY:

181175

AN XY:

721672

show subpopulations

Gnomad4 AFR exome

AF:

0.569

Gnomad4 AMR exome

AF:

0.325

Gnomad4 ASJ exome

AF:

0.299

Gnomad4 EAS exome

AF:

0.345

Gnomad4 SAS exome

AF:

0.210

Gnomad4 FIN exome

AF:

0.289

Gnomad4 NFE exome

AF:

0.235

Gnomad4 OTH exome

AF:

0.282

GnomAD4 genome

AF:

0.350

AC:

53085

AN:

151638

Hom.:

10596

Cov.:

AF XY:

0.348

AC XY:

25812

AN XY:

74076

show subpopulations

Gnomad4 AFR

AF:

0.555

Gnomad4 AMR

AF:

0.338

Gnomad4 ASJ

AF:

0.296

Gnomad4 EAS

AF:

0.388

Gnomad4 SAS

AF:

0.213

Gnomad4 FIN

AF:

0.282

Gnomad4 NFE

AF:

0.249

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.271

Hom.:

9991

Bravo

AF:

0.367

Asia WGS

AF:

0.322

AC:

1121

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Limb-Girdle Muscular Dystrophy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Caveolinopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.92

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