3-133448607-AAAG-A

Variant names:

• chr3-133448607-AAAG-A
• rs121908938
• NM_003571.4:c.697_699delGAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.79

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

ACMG classification

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 rank	MANE	Protein	UniProt
BFSP2	NM_003571.4	c.697_699delGAA	p.Glu233del	conservative_inframe_deletion	Exon 3 of 7	ENST00000302334.3	NP_003562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BFSP2	ENST00000302334.3	c.697_699delGAA	p.Glu233del	conservative_inframe_deletion	Exon 3 of 7	1	NM_003571.4	ENSP00000304987.2
BFSP2-AS1	ENST00000515542.1	n.282+171_282+173delCTT		intron_variant	Intron 3 of 4	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

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

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 12 multiple types Pathogenic:2

Nov 17, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant is also known as 696_698del (deltaE233). 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. This 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. -

not provided Pathogenic:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified 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

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The 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

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

Other links and lift over

dbSNP: rs121908938; hg19: chr3-133167451;