3-133448607-AAAG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_003571.4(BFSP2):​c.697_699delGAA​(p.Glu233del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BFSP2
NM_003571.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 4.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003571.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 3-133448607-AAAG-A is Pathogenic according to our data. Variant chr3-133448607-AAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 6584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133448607-AAAG-A is described in Lovd as [Likely_pathogenic]. Variant chr3-133448607-AAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BFSP2NM_003571.4 linkuse as main transcriptc.697_699delGAA p.Glu233del conservative_inframe_deletion 3/7 ENST00000302334.3 NP_003562.1 Q13515

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BFSP2ENST00000302334.3 linkuse as main transcriptc.697_699delGAA p.Glu233del conservative_inframe_deletion 3/71 NM_003571.4 ENSP00000304987.2 Q13515
BFSP2-AS1ENST00000515542.1 linkuse as main transcriptn.282+171_282+173delCTT intron_variant 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250540
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135416
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461744
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cataract 12 multiple types Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 17, 2004- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 06, 2022This variant is present in population databases (rs776669908, gnomAD 0.0009%). This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the BFSP2 protein (p.Glu233del), but otherwise preserves the integrity of the reading frame. This variant has been observed in individuals with autosomal dominant congenital cataract (PMID: 15570218, 27628848, 29914532; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant is also known as 696_698del (deltaE233). -
not provided Pathogenic:1Other:1
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 18, 2022Identified in multiple unrelated families with autosomal dominant congenital cataracts referred for testing at GeneDx and in published literature (Li et al., 2018; Jakobs et al., 2000; Zhang et al., 2004; Zhang et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19587458, 21042563, 21850182, 10634598, 29914532, 15570218, 17200662, 17490642, 27628848, 23288997, 17982427, 10739768) -
BFSP2-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 28, 2024The BFSP2 c.697_699delGAA variant is predicted to result in an in-frame deletion (p.Glu233del). This variant was reported to segregate with pediatric cataracts in three large unrelated families (Family ADCC-3 in Jakobs et al. 2000. PubMed ID: 10739768; Zhang et al. 2004. PubMed ID: 15570218; Family 11 in Li et al. 2018. PubMed ID: 29914532). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6584/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908938; hg19: chr3-133167451; API