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 id is 31739.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2, other=1}.
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3	c.-37G>A		5_prime_UTR_variant	Exon 1 of 2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5	c.-37G>A		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.-37G>A		5_prime_UTR_variant	Exon 1 of 2	1	NM_033337.3	ENSP00000341940.2

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tip-toe gait Pathogenic:1

-

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

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

Jun 27, 2011

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. -

not provided Other:1

Apr 15, 2012

Leiden Muscular Dystrophy (CAV3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

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;