rs797044871

Variant names:

• chr7-116559227-CTT-C
• rs797044871
• NM_001753.5:c.479_480delTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001753.5(CAV1):​c.479_480delTT​(p.Phe160fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV1 NM_001753.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.67
• Publications: 6 publications found

Genes affected

CAV1 (HGNC:1527): (caveolin 1) The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 mitogen-activated kinase cascade. Caveolin 1 and caveolin 2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Mutations in this gene have been associated with Berardinelli-Seip congenital lipodystrophy. Alternatively spliced transcripts encode alpha and beta isoforms of caveolin 1.[provided by RefSeq, Mar 2010]

CAV1 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital generalized lipodystrophy type 3

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, ClinGen
• partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pulmonary hypertension, primary, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• lipodystrophy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.108 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-116559227-CTT-C is Pathogenic according to our data. Variant chr7-116559227-CTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 208669.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001753.5. 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
	CAV1	NM_001753.5	MANE Select	c.479_480delTT	p.Phe160fs	frameshift	Exon 3 of 3	NP_001744.2
	CAV1	NM_001172895.1		c.386_387delTT	p.Phe129fs	frameshift	Exon 3 of 3	NP_001166366.1	Q59E85
	CAV1	NM_001172896.2		c.386_387delTT	p.Phe129fs	frameshift	Exon 2 of 2	NP_001166367.1	Q03135-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV1	ENST00000341049.7	TSL:1 MANE Select	c.479_480delTT	p.Phe160fs	frameshift	Exon 3 of 3	ENSP00000339191.2	Q03135-1
	CAV1	ENST00000393467.1	TSL:1	c.386_387delTT	p.Phe129fs	frameshift	Exon 2 of 2	ENSP00000377110.1	Q03135-2
	CAV1	ENST00000393468.1	TSL:1	c.386_387delTT	p.Phe129fs	frameshift	Exon 3 of 3	ENSP00000377111.1	Q03135-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital generalized lipodystrophy type 3;C3809192:Pulmonary hypertension, primary, 3 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs797044871; hg19: chr7-116199281;