3-8733883-G-A

Variant names:

• chr3-8733883-G-A
• rs1291499448
• NM_033337.3:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_033337.3(CAV3):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569
• Publications: 0 publications found

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]

SSUH2 Gene-Disease associations (from GenCC):

• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 14 pathogenic changes around while only 6 benign (70%) in NM_033337.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.83011 (below the threshold of 3.09). Trascript score misZ: 0.9876 (below the threshold of 3.09). GenCC associations: The gene is linked to rippling muscle disease 2, hypertrophic cardiomyopathy 1, long QT syndrome 9, distal myopathy, Tateyama type, inherited rippling muscle disease, Brugada syndrome, autosomal dominant limb-girdle muscular dystrophy type 1C, caveolinopathy, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34306145).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	NM_033337.3	MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.7G>A	p.Ala3Thr	missense	Exon 1 of 3	NP_001225.1	P56539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	ENST00000343849.3	TSL:1 MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.7G>A	p.Ala3Thr	missense	Exon 1 of 3	ENSP00000380525.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8576C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250940 AF XY: 0.00000737

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453074 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723370

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103952

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	0.0077	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.57
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.39
Sift	Benign	0.034	D
Sift4G	Uncertain	0.053	T
Polyphen		0.95	P
Vest4		0.10
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0215)
MVP		1.0
MPC		0.59
ClinPred		0.54	D
GERP RS		-0.25
PromoterAI		-0.089	Neutral
Varity_R		0.054
gMVP		0.73
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1291499448; hg19: chr3-8775569;