Genetic Variant BFSP2:p.Arg287Gly (chr3-133450432-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003571.4(BFSP2):c.859C>G(p.Arg287Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R287W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BFSP2
NM_003571.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.62

Publications

0 publications found

Variant links:

Genes affected

BFSP2 (HGNC:1041): (beaded filament structural protein 2) More than 99% of the vertebrate ocular lens is comprised of terminally differentiated lens fiber cells. Two lens-specific intermediate filament-like proteins, the protein product of this gene (phakinin), and filensin, are expressed only after fiber cell differentiation has begun. Both proteins are found in a structurally unique cytoskeletal element that is referred to as the beaded filament (BF). Mutations in this gene have been associated with juvenile-onset, progressive cataracts and Dowling-Meara epidermolysis bullosa simplex. [provided by RefSeq, Jun 2009]

BFSP2 links:

BFSP2-AS1 (HGNC:28425): (BFSP2 antisense RNA 1)

BFSP2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003571.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BFSP2	NM_003571.4	MANE Select	c.859C>G	p.Arg287Gly	missense	Exon 4 of 7	NP_003562.1
BFSP2-AS1	NR_135276.2		n.344-1537G>C		intron	N/A
BFSP2-AS1	NR_135277.2		n.344-4857G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BFSP2	ENST00000302334.3	TSL:1 MANE Select	c.859C>G	p.Arg287Gly	missense	Exon 4 of 7	ENSP00000304987.2
BFSP2-AS1	ENST00000515542.1	TSL:1	n.168-1537G>C		intron	N/A
BFSP2	ENST00000510039.1	TSL:3	n.10C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Benign

0.070

Eigen_PC

Benign

0.0083

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.86

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.3

PhyloP100

1.6

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.48

Vest4

0.76

MutPred

0.71

Loss of MoRF binding (P = 0.0854)

MVP

0.85

MPC

0.61

ClinPred

0.99

GERP RS

2.4

Varity_R

0.79

gMVP

0.71

Mutation Taster

=30/70

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over