3-8733903-C-T

Variant names:

• chr3-8733903-C-T
• rs1974763
• NM_033337.3:c.27C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033337.3(CAV3):​c.27C>T​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,610,152 control chromosomes in the GnomAD database, including 11,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.082 (683 hom., cov: 31)
  • Exomes 𝑓: 0.11 (11092 hom.)
• Consequence: CAV3 NM_033337.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.0920
• Publications: 17 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-8733903-C-T is Benign according to our data. Variant chr3-8733903-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

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.27C>T	p.Leu9Leu	synonymous	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.27C>T	p.Leu9Leu	synonymous	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.27C>T	p.Leu9Leu	synonymous	Exon 1 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.27C>T	p.Leu9Leu	synonymous	Exon 1 of 3	ENSP00000380525.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8556G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12501 AN: 151930 Hom.: 683 Cov.: 31

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.0930

GnomAD2 exomes AF: 0.0855 AC: 21481 AN: 251102 AF XY: 0.0859

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0535

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.115 AC: 167363 AN: 1458104 Hom.: 11092 Cov.: 30 AF XY: 0.112 AC XY: 81473 AN XY: 725622

African (AFR) AF: 0.0185 AC: 618 AN: 33450

American (AMR) AF: 0.0560 AC: 2504 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 1723 AN: 26118

East Asian (EAS) AF: 0.00151 AC: 60 AN: 39696

South Asian (SAS) AF: 0.0272 AC: 2347 AN: 86186

European-Finnish (FIN) AF: 0.114 AC: 6076 AN: 53406

Middle Eastern (MID) AF: 0.0564 AC: 325 AN: 5766

European-Non Finnish (NFE) AF: 0.134 AC: 148035 AN: 1108488

Other (OTH) AF: 0.0941 AC: 5675 AN: 60288

GnomAD4 genome AF: 0.0822 AC: 12502 AN: 152048 Hom.: 683 Cov.: 31 AF XY: 0.0789 AC XY: 5861 AN XY: 74306

African (AFR) AF: 0.0221 AC: 918 AN: 41510

American (AMR) AF: 0.0759 AC: 1159 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5168

South Asian (SAS) AF: 0.0267 AC: 128 AN: 4800

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10568

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.127 AC: 8650 AN: 67960

Other (OTH) AF: 0.0920 AC: 194 AN: 2108

Alfa AF: 0.110 Hom.: 2004

Bravo AF: 0.0779

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Caveolinopathy (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.092
PromoterAI		-0.0090	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1974763; hg19: chr3-8775589; COSMIC: COSV59561905;