17-42403689-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012232.6(CAVIN1):c.*998G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 152,056 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAVIN1 NM_012232.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.606

Genes affected

CAVIN1 (HGNC:9688): (caveolae associated protein 1) This gene encodes a protein that enables the dissociation of paused ternary polymerase I transcription complexes from the 3' end of pre-rRNA transcripts. This protein regulates rRNA transcription by promoting the dissociation of transcription complexes and the reinitiation of polymerase I on nascent rRNA transcripts. This protein also localizes to caveolae at the plasma membrane and is thought to play a critical role in the formation of caveolae and the stabilization of caveolins. This protein translocates from caveolae to the cytoplasm after insulin stimulation. Caveolae contain truncated forms of this protein and may be the site of phosphorylation-dependent proteolysis. This protein is also thought to modify lipid metabolism and insulin-regulated gene expression. Mutations in this gene result in a disorder characterized by generalized lipodystrophy and muscular dystrophy. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-42403689-C-T is Benign according to our data. Variant chr17-42403689-C-T is described in ClinVar as [Benign]. Clinvar id is 889074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00753 (1145/152056) while in subpopulation AMR AF= 0.016 (244/15278). AF 95% confidence interval is 0.0143. There are 7 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN1	NM_012232.6	c.*998G>A		3_prime_UTR_variant	2/2	ENST00000357037.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN1	ENST00000357037.6	c.*998G>A		3_prime_UTR_variant	2/2	1	NM_012232.6	P1

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1145 AN: 151936 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0172

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00481 AC: 3 AN: 624 Hom.: 0 Cov.: 0 AF XY: 0.00711 AC XY: 3 AN XY: 422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00753 AC: 1145 AN: 152056 Hom.: 7 Cov.: 31 AF XY: 0.00774 AC XY: 575 AN XY: 74312

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00688 Hom.: 0

Bravo AF: 0.00901

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital generalized lipodystrophy type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.51
Dann	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs35725766; hg19: chr17-40555707;