Genetic Variant BFSP1:p.Ala592Val (chr20-17494297-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001195.5(BFSP1):c.1775C>T(p.Ala592Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000681 in 1,614,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00068 ( 3 hom. )

Consequence

BFSP1
NM_001195.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.934

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043178797).

BP6

Variant 20-17494297-G-A is Benign according to our data. Variant chr20-17494297-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 474090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000709 (108/152286) while in subpopulation SAS AF = 0.00124 (6/4828). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BFSP1	NM_001195.5	MANE Select	c.1775C>T	p.Ala592Val	missense	Exon 8 of 8	NP_001186.1	Q12934-1
BFSP1	NM_001424338.1		c.1667C>T	p.Ala556Val	missense	Exon 7 of 7	NP_001411267.1
BFSP1	NM_001278607.2		c.1442C>T	p.Ala481Val	missense	Exon 8 of 8	NP_001265536.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BFSP1	ENST00000377873.8	TSL:1 MANE Select	c.1775C>T	p.Ala592Val	missense	Exon 8 of 8	ENSP00000367104.3	Q12934-1
BFSP1	ENST00000377868.6	TSL:1	c.1400C>T	p.Ala467Val	missense	Exon 8 of 8	ENSP00000367099.2	Q12934-2
BFSP1	ENST00000929672.1		c.1667C>T	p.Ala556Val	missense	Exon 7 of 7	ENSP00000599731.1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000863

AC:

217

AN:

251360

AF XY:

0.000927

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.000679

AC:

992

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000663

AC XY:

482

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

173

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00105

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000536

AC:

596

AN:

1112002

Other (OTH)

AF:

0.00119

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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

AF:

0.000709

AC:

108

AN:

152286

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41560

American (AMR)

AF:

0.000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000887

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000972

AC:

118

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

BFSP1-related disorder (1)

Cataract 33 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.042

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.056

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.38

M_CAP

Benign

0.0030

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

-0.93

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.86

REVEL

Benign

0.026

Sift

Benign

0.37

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.028

MVP

0.061

MPC

0.073

ClinPred

0.00072

GERP RS

-8.3

Varity_R

0.020

gMVP

0.087

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over