NM_033337.3:c.32C>T

Variant names:

• chr3-8733908-C-T
• rs867194464
• NM_033337.3:c.32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 5P and 3B. PM1 PM2 PP2 BP4_Moderate BP6

The NM_033337.3(CAV3):​c.32C>T​(p.Ala11Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,074 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.59
• 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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain 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=0.20604691).
• BP6: Variant 3-8733908-C-T is Benign according to our data. Variant chr3-8733908-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 519540.

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.32C>T	p.Ala11Val	missense	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.32C>T	p.Ala11Val	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.32C>T	p.Ala11Val	missense	Exon 1 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.32C>T	p.Ala11Val	missense	Exon 1 of 3	ENSP00000380525.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8551G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.41
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		0.091	B
Vest4		0.25
MutPred		0.54		Loss of helix (P = 0.0033)
MVP		1.0
MPC		0.57
ClinPred		0.40	T
GERP RS		4.8
PromoterAI		-0.086	Neutral
Varity_R		0.062
gMVP		0.52
Mutation Taster		=82/18	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: rs867194464; hg19: chr3-8775594;