dbSNP rs1354029651: CAV3:c.114+5G>A (chr3-8733995-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_033337.3(CAV3):c.114+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CAV3
NM_033337.3 splice_region, intron

Scores

Splicing: ADA: 0.9978

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3 link	c.114+5G>A		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 link	c.114+5G>A		splice_region_variant, 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.114+5G>A		splice_region_variant, intron_variant	Intron 1 of 1	1	NM_033337.3	ENSP00000341940.2		P56539

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250272

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699712

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31808

American (AMR)

AF:

0.00

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25722

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00

AC:

AN:

85118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

9.48e-7

AC:

AN:

1054934

Other (OTH)

AF:

0.00

AC:

AN:

58396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

2.3

PromoterAI

-0.17

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.57

Position offset: 36

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over