Genetic Variant NM_033337.3:c.115-4806A>G (chr3-8740720-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033337.3(CAV3):c.115-4806A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,988 control chromosomes in the GnomAD database, including 20,062 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 20062 hom., cov: 32)

Consequence

CAV3
NM_033337.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0820

Publications

11 publications found

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

SSUH2 Gene-Disease associations (from GenCC):

dentin dysplasia type I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SSUH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3 link	c.115-4806A>G		intron_variant	Intron 1 of 1	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 link	c.115-4806A>G		intron_variant	Intron 1 of 2		NP_001225.1	P56539

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3 link	c.115-4806A>G		intron_variant	Intron 1 of 1	1	NM_033337.3	ENSP00000341940.2		P56539

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78176

AN:

151868

Hom.:

20030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.529

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.539

Gnomad ASJ

AF:

0.421

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.470

Gnomad FIN

AF:

0.489

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.523

Gnomad OTH

AF:

0.518

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.515

AC:

78257

AN:

151988

Hom.:

20062

Cov.:

AF XY:

0.513

AC XY:

38066

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.529

AC:

21937

AN:

41462

American (AMR)

AF:

0.539

AC:

8233

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

1462

AN:

3470

East Asian (EAS)

AF:

0.394

AC:

2029

AN:

5154

South Asian (SAS)

AF:

0.472

AC:

2270

AN:

4814

European-Finnish (FIN)

AF:

0.489

AC:

5158

AN:

10556

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.523

AC:

35504

AN:

67928

Other (OTH)

AF:

0.514

AC:

1086

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2009

4019

6028

8038

10047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.512

Hom.:

58873

Bravo

AF:

0.514

Asia WGS

AF:

0.442

AC:

1535

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.2

(source)

DANN

Benign

0.60

PhyloP100

0.082

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over