rs79087781

Variant names:

• chr3-133472541-C-A
• rs79087781
• NM_003571.4:c.1220C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003571.4(BFSP2):​c.1220C>A​(p.Ala407Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,612,172 control chromosomes in the GnomAD database, including 1,686 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (137 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1549 hom.)
• Consequence: BFSP2 NM_003571.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.09

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007096857).
• BP6: Variant 3-133472541-C-A is Benign according to our data. Variant chr3-133472541-C-A is described in ClinVar as [Benign]. Clinvar id is 259089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BFSP2	NM_003571.4	c.1220C>A	p.Ala407Asp	missense_variant	Exon 6 of 7	ENST00000302334.3	NP_003562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BFSP2	ENST00000302334.3	c.1220C>A	p.Ala407Asp	missense_variant	Exon 6 of 7	1	NM_003571.4	ENSP00000304987.2
BFSP2	ENST00000503047.1	n.200C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
BFSP2	ENST00000510039.1	n.365C>A		non_coding_transcript_exon_variant	Exon 3 of 4	3
BFSP2	ENST00000511434.1	n.*26C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6287 AN: 152212 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0622

GnomAD2 exomes AF: 0.0447 AC: 10991 AN: 245866 AF XY: 0.0471

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.0277

Gnomad FIN exome AF: 0.0451

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0438 AC: 63893 AN: 1459842 Hom.: 1549 Cov.: 33 AF XY: 0.0446 AC XY: 32420 AN XY: 726220

Gnomad4 AFR exome AF: 0.0361 AC: 1206 AN: 33420

Gnomad4 AMR exome AF: 0.0275 AC: 1227 AN: 44666

Gnomad4 ASJ exome AF: 0.0686 AC: 1790 AN: 26104

Gnomad4 EAS exome AF: 0.0182 AC: 724 AN: 39692

Gnomad4 SAS exome AF: 0.0639 AC: 5506 AN: 86130

Gnomad4 FIN exome AF: 0.0450 AC: 2400 AN: 53366

Gnomad4 NFE exome AF: 0.0431 AC: 47949 AN: 1111846

Gnomad4 Remaining exome AF: 0.0460 AC: 2767 AN: 60204

GnomAD4 genome AF: 0.0414 AC: 6299 AN: 152330 Hom.: 137 Cov.: 33 AF XY: 0.0411 AC XY: 3064 AN XY: 74480

Gnomad4 AFR AF: 0.0358 AC: 0.0358294 AN: 0.0358294

Gnomad4 AMR AF: 0.0355 AC: 0.0354763 AN: 0.0354763

Gnomad4 ASJ AF: 0.0691 AC: 0.0691244 AN: 0.0691244

Gnomad4 EAS AF: 0.0234 AC: 0.0233501 AN: 0.0233501

Gnomad4 SAS AF: 0.0582 AC: 0.0582263 AN: 0.0582263

Gnomad4 FIN AF: 0.0461 AC: 0.0461481 AN: 0.0461481

Gnomad4 NFE AF: 0.0437 AC: 0.0437346 AN: 0.0437346

Gnomad4 OTH AF: 0.0634 AC: 0.063447 AN: 0.063447

Alfa AF: 0.0450 Hom.: 550

Bravo AF: 0.0411

TwinsUK AF: 0.0423 AC: 157

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.0441 AC: 379

ExAC AF: 0.0443 AC: 5372

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.0481

EpiControl AF: 0.0485

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cataract 12 multiple types Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.59	T
Sift4G	Uncertain	0.047	D
Polyphen		0.92	P
Vest4		0.16
MPC		0.67
ClinPred		0.019	T
GERP RS		2.3
Varity_R		0.45
gMVP		0.43
Mutation Taster		=81/19	polymorphism (auto)

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: rs79087781; hg19: chr3-133191385; COSMIC: COSV56587633; COSMIC: COSV56587633;