rs1085307126

chr20-17496938-C-Achr20-17496938-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_001195.5(BFSP1):c.1042G>T(p.Asp348Tyr) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D348N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BFSP1 NM_001195.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62

Genes affected

BFSP1 (HGNC:1040): (beaded filament structural protein 1) This gene encodes a lens-specific intermediate filament-like protein named filensin. The encoded protein is expressed in lens fiber cells after differentiation has begun. This protein functions as a component of the beaded filament which is a cytoskeletal structure found in lens fiber cells. Mutations in this gene are the cause of autosomal recessive cortical juvenile-onset cataract. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-17496938-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 425558.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BFSP1	NM_001195.5	c.1042G>T	p.Asp348Tyr	missense_variant, splice_region_variant	7/8	ENST00000377873.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BFSP1	ENST00000377873.8	c.1042G>T	p.Asp348Tyr	missense_variant, splice_region_variant	7/8	1	NM_001195.5	P1
BFSP1	ENST00000377868.6	c.667G>T	p.Asp223Tyr	missense_variant, splice_region_variant	7/8	1
BFSP1	ENST00000536626.7	c.625G>T	p.Asp209Tyr	missense_variant, splice_region_variant	8/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1380730 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 680922

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.70
MutPred		0.65		Loss of disorder (P = 0.0143);.;.;
MVP		0.99
MPC		0.46
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1085307126; hg19: chr20-17477583;