3-133400158-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003571.4(BFSP2):c.75G>A(p.Ala25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,140 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (21 hom.)
• Consequence: BFSP2 NM_003571.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.38

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-133400158-G-A is Benign according to our data. Variant chr3-133400158-G-A is described in ClinVar as [Benign]. Clinvar id is 343398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00142 (217/152324) while in subpopulation EAS AF= 0.0267 (138/5178). AF 95% confidence interval is 0.023. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BFSP2	NM_003571.4	c.75G>A	p.Ala25=	synonymous_variant	1/7	ENST00000302334.3
BFSP2	XM_017007315.2	c.75G>A	p.Ala25=	synonymous_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BFSP2	ENST00000302334.3	c.75G>A	p.Ala25=	synonymous_variant	1/7	1	NM_003571.4	P1
BFSP2	ENST00000513441.1	n.85G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.0268

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00271 AC: 682 AN: 251210 Hom.: 18 AF XY: 0.00258 AC XY: 350 AN XY: 135778

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.0265

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00117 AC: 1707 AN: 1461816 Hom.: 21 Cov.: 31 AF XY: 0.00123 AC XY: 896 AN XY: 727198

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00142 AC: 217 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74468

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 12 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.16
Dann	Benign	0.75

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: rs146992682; hg19: chr3-133119002; COSMIC: COSV56586489; COSMIC: COSV56586489;