Variant 3-133448607-AAAG-A details in Genebe, Genetics Data Aggregator

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_699del(p.Glu233del) variant causes a 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 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]

BFSP2 links:

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

BFSP2-AS1 links:

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
BFSP2	NM_003571.4 linkuse as main transcript	c.697_699del	p.Glu233del	inframe_deletion	3/7	ENST00000302334.3	NP_003562.1
BFSP2-AS1	NR_135277.1 linkuse as main transcript	n.381-3035_381-3033del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BFSP2	ENST00000302334.3 linkuse as main transcript	c.697_699del	p.Glu233del	inframe_deletion	3/7	1	NM_003571.4	ENSP00000304987	P1
BFSP2-AS1	ENST00000515542.1 linkuse as main transcript	n.282+171_282+173del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250540

Hom.:

AF XY:

0.00000738

AC XY:

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:

AN:

1461744

Hom.:

AF XY:

0.00000138

AC XY:

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.:

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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 06, 2022	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. 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2004	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over