rs140575619

Variant names:

• chr3-8745854-G-A
• rs140575619
• NM_033337.3:c.443G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_033337.3(CAV3):​c.443G>A​(p.Arg148Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,611,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: 5.54
• Publications: 10 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]

OXTR (HGNC:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• 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 distal myopathy, Tateyama type, caveolinopathy, inherited rippling muscle disease, autosomal dominant limb-girdle muscular dystrophy type 1C, long QT syndrome, long QT syndrome 9, Brugada syndrome, rippling muscle disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02571112).
• BP6: Variant 3-8745854-G-A is Benign according to our data. Variant chr3-8745854-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96240.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000486 (74/152330) while in subpopulation AMR AF = 0.00131 (20/15306). AF 95% confidence interval is 0.000958. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.443G>A	p.Arg148Gln	missense	Exon 2 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.443G>A	p.Arg148Gln	missense	Exon 2 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.443G>A	p.Arg148Gln	missense	Exon 2 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.443G>A	p.Arg148Gln	missense	Exon 2 of 3	ENSP00000380525.2	P56539
	CAV3	ENST00000472766.1	TSL:2	n.155+11864G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000249 AC: 62 AN: 249176 AF XY: 0.000178

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000884 AC: 129 AN: 1459274 Hom.: 0 Cov.: 32 AF XY: 0.0000799 AC XY: 58 AN XY: 725672

African (AFR) AF: 0.000986 AC: 33 AN: 33460

American (AMR) AF: 0.000895 AC: 40 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52000

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1110974

Other (OTH) AF: 0.000149 AC: 9 AN: 60348

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74480

African (AFR) AF: 0.00123 AC: 51 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	4	not provided (7)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CAV3-related disorder (1)
-	-	1	Caveolinopathy (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Benign	0.76
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.54	N
PhyloP100		5.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.46
Sift	Benign	0.70	T
Sift4G	Benign	0.68	T
Polyphen		0.083	B
Vest4		0.32
MVP		0.94
MPC		0.78
ClinPred		0.095	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.72
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: rs140575619; hg19: chr3-8787540; COSMIC: COSV57478606; COSMIC: COSV57478606;