Genetic Variant BBS1:p.Val582Phe (chr11-66531999-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024649.5(BBS1):c.1744G>T(p.Val582Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,034 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V582I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BBS1
NM_024649.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.88

Publications

0 publications found

Variant links:

Genes affected

BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

BBS1 links:

ENSG00000256349 (HGNC:):

ENSG00000256349 links:

ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS1	NM_024649.5 link	c.1744G>T	p.Val582Phe	missense_variant	Exon 17 of 17	ENST00000318312.12	NP_078925.3	Q8NFJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12 link	c.1744G>T	p.Val582Phe	missense_variant	Exon 17 of 17	1	NM_024649.5	ENSP00000317469.7		Q8NFJ9-1
ENSG00000256349	ENST00000419755.3 link	c.1855G>T	p.Val619Phe	missense_variant	Exon 17 of 17	2		ENSP00000398526.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

239438

AF XY:

0.00000771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000927

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456034

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25972

East Asian (EAS)

AF:

0.00

AC:

AN:

39458

South Asian (SAS)

AF:

0.00

AC:

AN:

85518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109958

Other (OTH)

AF:

0.00

AC:

AN:

60026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;D;T

Eigen

Benign

-0.048

Eigen_PC

Benign

-0.036

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.4

.;L;.

PhyloP100

4.9

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.49, 0.99

.;P;D

Vest4

0.53

MutPred

0.42

.;Gain of helix (P = 0.132);.;

MVP

0.91

MPC

0.31

ClinPred

0.89

GERP RS

2.7

Varity_R

0.51

gMVP

0.86

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over