rs121909281

chr3-8733916-G-Achr3-8733916-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BS1 BS2

The NM_033337.3(CAV3):c.40G>A(p.Val14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,613,380 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V14L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.738

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 Benign. Variant got -9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-8733916-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 8295.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010237575).
• BP6: Variant 3-8733916-G-A is Benign according to our data. Variant chr3-8733916-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162827.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=2}. Variant chr3-8733916-G-A is described in Lovd as [Benign]. Variant chr3-8733916-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-8733916-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000828 (126/152194) while in subpopulation AFR AF= 0.0025 (104/41552). AF 95% confidence interval is 0.00211. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 127 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.40G>A	p.Val14Ile	missense_variant	1/2	ENST00000343849.3
CAV3	NM_001234.5	c.40G>A	p.Val14Ile	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.40G>A	p.Val14Ile	missense_variant	1/2	1	NM_033337.3	P1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000434 AC: 109 AN: 251318 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135848

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461186 Hom.: 2 Cov.: 30 AF XY: 0.000242 AC XY: 176 AN XY: 726956

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.000739 AC XY: 55 AN XY: 74406

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.00100

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CAV3: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	This variant is associated with the following publications: (PMID: 25351510, 27312022, 26159999, 27066573) -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2014	Val14Ile in exon 1 of CAV3: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (14/4406) of African American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs121909281). In addition, this variant is not conserved in mammals and of note, multiple mammals have an isoleucine (Ile) at this position despite hig h nearby amino acid conservation. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2019	Variant summary: CAV3 c.40G>A (p.Val14Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251318 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAV3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.40G>A, has been reported in the literature in individuals with exercise intolerance and rhabdomyolysis, LQTS, HCM or dysferlinopathy (Scalco_2016, Ghouse_2015, Lopes_2015, Izumi_2015). The patient diagnosed with dyserflinopathy also carried another likely pathogenic DYSF variant, c.1667C>T (p.L556P)(Izumi_2005). One publication, Scalco_2016, reports that immunohistochemistry indicated Caveolin-3 was normal but western blot showed expression level of Caeolin-3 was decreased. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 01, 2020

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2018

This alteration is classified as likely 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
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.37	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.011	B;B
Vest4		0.41
MVP		0.83
MPC		0.43
ClinPred		0.012	T
GERP RS		1.4
Varity_R		0.032
gMVP		0.51

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: rs121909281; hg19: chr3-8775602;