rs11476

chr3-8746512-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033337.3(CAV3):c.*645A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 151,820 control chromosomes in the GnomAD database, including 13,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13442 hom., cov: 30)
  • Exomes 𝑓: 0.36 (5 hom.)
• Consequence: CAV3 NM_033337.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.110

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-8746512-A-T is Benign according to our data. Variant chr3-8746512-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 31706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.*645A>T		3_prime_UTR_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.*549A>T		3_prime_UTR_variant	3/3
OXTR	XR_007095681.1	n.1885-3910T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.*645A>T		3_prime_UTR_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.*549A>T		3_prime_UTR_variant	3/3	1		P1
CAV3	ENST00000472766.1	n.155+12522A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63064 AN: 151636 Hom.: 13436 Cov.: 30

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.364 AC: 24 AN: 66 Hom.: 5 Cov.: 0 AF XY: 0.325 AC XY: 13 AN XY: 40

Gnomad4 AMR exome AF: 0.333

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.416 AC: 63115 AN: 151754 Hom.: 13442 Cov.: 30 AF XY: 0.416 AC XY: 30844 AN XY: 74124

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.398

Alfa AF: 0.435 Hom.: 1949

Bravo AF: 0.412

Asia WGS AF: 0.281 AC: 978 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.3
Dann	Benign	0.57

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: rs11476; hg19: chr3-8788198;