3-133400329-T-C

Position:

• chr3-133400329-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003571.4(BFSP2):​c.246T>C​(p.Ser82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,030 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: BFSP2 NM_003571.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.503

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-133400329-T-C is Benign according to our data. Variant chr3-133400329-T-C is described in ClinVar as [Benign]. Clinvar id is 343401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133400329-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.503 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BFSP2	NM_003571.4	c.246T>C	p.Ser82=	synonymous_variant	1/7	ENST00000302334.3	NP_003562.1
BFSP2	XM_017007315.2	c.246T>C	p.Ser82=	synonymous_variant	1/6		XP_016862804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BFSP2	ENST00000302334.3	c.246T>C	p.Ser82=	synonymous_variant	1/7	1	NM_003571.4	ENSP00000304987	P1
BFSP2	ENST00000513441.1	n.256T>C		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00166 AC: 416 AN: 251144 Hom.: 7 AF XY: 0.00205 AC XY: 278 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00849

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00122 AC: 1783 AN: 1461696 Hom.: 10 Cov.: 31 AF XY: 0.00148 AC XY: 1073 AN XY: 727142

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00865

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000737

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74488

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000752

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 12 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.8
DANN	Benign	0.61

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: rs145934653; hg19: chr3-133119173;