rs148066554

Variant names:

• chr7-116525108-G-A
• rs148066554
• NM_001753.5:c.30+16G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116525108-G-A
• chr7-116525108-G-C
• chr7-116525108-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001172895.1(CAV1):​c.-761G>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 0.00326 in 1,614,228 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (13 hom.)
• Consequence: CAV1 NM_001172895.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.736
• Publications: 2 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):

• congenital generalized lipodystrophy type 3

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 7-116525108-G-A is Benign according to our data. Variant chr7-116525108-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 995628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (302/152356) while in subpopulation NFE AF = 0.00367 (250/68040). AF 95% confidence interval is 0.0033. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172895.1. 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.30+16G>A		intron	N/A	NP_001744.2
	CAV1	NM_001172895.1		c.-761G>A		5_prime_UTR	Exon 1 of 3	NP_001166366.1	Q59E85

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV1	ENST00000341049.7	TSL:1 MANE Select	c.30+16G>A		intron	N/A	ENSP00000339191.2	Q03135-1
	CAV1	ENST00000614113.5	TSL:1	c.30+16G>A		intron	N/A	ENSP00000479447.2	A0A7P0YWJ6
	CAV1	ENST00000451122.5	TSL:1	n.46G>A		non_coding_transcript_exon	Exon 1 of 3	ENSP00000409541.1	F8WDM7

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00182 AC: 454 AN: 249776 AF XY: 0.00176

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00339 AC: 4959 AN: 1461872 Hom.: 13 Cov.: 31 AF XY: 0.00335 AC XY: 2438 AN XY: 727238

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00170 AC: 147 AN: 86258

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00410 AC: 4555 AN: 1111996

Other (OTH) AF: 0.00262 AC: 158 AN: 60394

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74502

African (AFR) AF: 0.000601 AC: 25 AN: 41590

American (AMR) AF: 0.000261 AC: 4 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00367 AC: 250 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.00195

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Pulmonary hypertension, primary, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.9
DANN	Benign	0.92
PhyloP100		0.74
PromoterAI		-0.051	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148066554; hg19: chr7-116165162; COSMIC: COSV61952606;