3-8733844-G-T

Variant names:

• chr3-8733844-G-T
• rs72546666
• NM_033337.3:c.-33G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_033337.3(CAV3):​c.-33G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,372,802 control chromosomes in the GnomAD database, including 2 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 0.00043 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: CAV3 NM_033337.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -6.43
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-8733844-G-T is Benign according to our data. Variant chr3-8733844-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180795.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000434 (66/152176) while in subpopulation EAS AF = 0.0126 (65/5164). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3	c.-33G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000343849.3	NP_203123.1
CAV3	NM_033337.3	c.-33G>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5	c.-33G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3		NP_001225.1
CAV3	NM_001234.5	c.-33G>T		5_prime_UTR_variant	Exon 1 of 3		NP_001225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3	c.-33G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_033337.3	ENSP00000341940.2
CAV3	ENST00000343849.3	c.-33G>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_033337.3	ENSP00000341940.2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152056 Hom.: 1 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: 0.0126

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

GnomAD2 exomes AF: 0.000846 AC: 207 AN: 244644 AF XY: 0.000795

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000388 AC: 474 AN: 1220626 Hom.: 1 Cov.: 17 AF XY: 0.000370 AC XY: 229 AN XY: 618848

African (AFR) AF: 0.00 AC: 0 AN: 28836

American (AMR) AF: 0.0000228 AC: 1 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24556

East Asian (EAS) AF: 0.0116 AC: 448 AN: 38564

South Asian (SAS) AF: 0.0000739 AC: 6 AN: 81178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000224 AC: 2 AN: 892796

Other (OTH) AF: 0.000324 AC: 17 AN: 52516

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152176 Hom.: 1 Cov.: 31 AF XY: 0.000578 AC XY: 43 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.0126 AC: 65 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000468

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Limb-Girdle Muscular Dystrophy, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Caveolinopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.097
DANN	Benign	0.64
PhyloP100		-6.4
PromoterAI		-0.032	Neutral
Mutation Taster		=299/1	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: rs72546666; hg19: chr3-8775530;