3-8733840-G-A

Variant names:

• chr3-8733840-G-A
• rs116840771
• NM_033337.3:c.-37G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033337.3(CAV3):​c.-37G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,333,412 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: CAV3 NM_033337.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2 O:1
• Conservation: PhyloP100: 1.26
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-8733840-G-A is Benign according to our data. Variant chr3-8733840-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31739.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00273 (416/152266) while in subpopulation NFE AF = 0.00396 (269/68012). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

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.-37G>A		5_prime_UTR	Exon 1 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.-37G>A		5_prime_UTR	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.-37G>A		5_prime_UTR	Exon 1 of 2	ENSP00000341940.2	P56539
	SSUH2	ENST00000478513.1	TSL:1	n.335+8619C>T		intron	N/A
	SSUH2	ENST00000435138.5	TSL:2	c.-1126+8619C>T		intron	N/A	ENSP00000412333.2	Q9Y2M2-3

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00275 AC: 667 AN: 242286 AF XY: 0.00261

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.000892

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00676

Gnomad NFE exome AF: 0.00340

Gnomad OTH exome AF: 0.00550

GnomAD4 exome AF: 0.00384 AC: 4539 AN: 1181146 Hom.: 17 Cov.: 16 AF XY: 0.00382 AC XY: 2293 AN XY: 600848

African (AFR) AF: 0.000532 AC: 15 AN: 28182

American (AMR) AF: 0.00106 AC: 46 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.00412 AC: 100 AN: 24274

East Asian (EAS) AF: 0.00 AC: 0 AN: 38386

South Asian (SAS) AF: 0.00124 AC: 100 AN: 80326

European-Finnish (FIN) AF: 0.00765 AC: 404 AN: 52842

Middle Eastern (MID) AF: 0.00816 AC: 43 AN: 5272

European-Non Finnish (NFE) AF: 0.00428 AC: 3666 AN: 857020

Other (OTH) AF: 0.00322 AC: 165 AN: 51262

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152266 Hom.: 0 Cov.: 31 AF XY: 0.00262 AC XY: 195 AN XY: 74444

African (AFR) AF: 0.00113 AC: 47 AN: 41548

American (AMR) AF: 0.00183 AC: 28 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00396 AC: 269 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00289 Hom.: 2

Bravo AF: 0.00241

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Caveolinopathy (1)
-	1	-	Congenital long QT syndrome (1)
-	1	-	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	not specified (1)
1	-	-	Tip-toe gait (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.3
DANN	Benign	0.47
PhyloP100		1.3
PromoterAI		-0.034	Neutral
Mutation Taster		=300/0	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: rs116840771; hg19: chr3-8775526; COSMIC: COSV59562202; COSMIC: COSV59562202;