dbSNP rs143850362: BFSP1:p.Gly46Val (chr20-17531193-C-A) – 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_001195.5(BFSP1):c.137G>T(p.Gly46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,152,586 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. G46W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

BFSP1
NM_001195.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Publications

0 publications found

Variant links:

Genes affected

BFSP1 (HGNC:1040): (beaded filament structural protein 1) This gene encodes a lens-specific intermediate filament-like protein named filensin. The encoded protein is expressed in lens fiber cells after differentiation has begun. This protein functions as a component of the beaded filament which is a cytoskeletal structure found in lens fiber cells. Mutations in this gene are the cause of autosomal recessive cortical juvenile-onset cataract. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

BFSP1 Gene-Disease associations (from GenCC):

cataract 33
Inheritance: AR, AD, SD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BFSP1 links:

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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
BFSP1	NM_001195.5 link	c.137G>T	p.Gly46Val	missense_variant	Exon 1 of 8	ENST00000377873.8	NP_001186.1	Q12934-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BFSP1	ENST00000377873.8 link	c.137G>T	p.Gly46Val	missense_variant	Exon 1 of 8	1	NM_001195.5	ENSP00000367104.3	Q12934-1
BFSP1	ENST00000377868.6 link	c.3-6285G>T		intron_variant	Intron 1 of 7	1		ENSP00000367099.2	Q12934-2
BFSP1	ENST00000536626.7 link	c.-40-6285G>T		intron_variant	Intron 2 of 8	2		ENSP00000442522.1	Q12934-3
BFSP1	ENST00000473415.1 link	n.472-6285G>T		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000260

AC:

AN:

1152586

Hom.:

Cov.:

AF XY:

0.00000179

AC XY:

AN XY:

557982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23126

American (AMR)

AF:

0.00

AC:

AN:

10890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15502

East Asian (EAS)

AF:

0.00

AC:

AN:

25646

South Asian (SAS)

AF:

0.00

AC:

AN:

41878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3162

European-Non Finnish (NFE)

AF:

0.00000312

AC:

AN:

960184

Other (OTH)

AF:

0.00

AC:

AN:

46068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.047

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.4

PhyloP100

2.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.52

Sift

Benign

0.22

Sift4G

Benign

0.14

Polyphen

0.85

Vest4

0.36

MutPred

0.55

Loss of catalytic residue at G46 (P = 0.0322);

MVP

0.94

MPC

2.1

ClinPred

0.95

GERP RS

1.6

PromoterAI

-0.26

Neutral

(source)

Varity_R

0.085

gMVP

0.32

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over