20-17496938-C-T

Variant names:

• chr20-17496938-C-T
• rs1085307126
• NM_001195.5:c.1042G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001195.5(BFSP1):​c.1042G>A​(p.Asp348Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000724 in 1,380,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BFSP1 NM_001195.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.62
• Publications: 7 publications found

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]

BFSP1 Gene-Disease associations (from GenCC):

• cataract 33

  Inheritance: AR, AD, SD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-17496938-C-T is Pathogenic according to our data. Variant chr20-17496938-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 425558.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BFSP1	NM_001195.5	MANE Select	c.1042G>A	p.Asp348Asn	missense splice_region	Exon 7 of 8	NP_001186.1
	BFSP1	NM_001424338.1		c.934G>A	p.Asp312Asn	missense splice_region	Exon 6 of 7	NP_001411267.1
	BFSP1	NM_001278607.2		c.709G>A	p.Asp237Asn	missense splice_region	Exon 7 of 8	NP_001265536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BFSP1	ENST00000377873.8	TSL:1 MANE Select	c.1042G>A	p.Asp348Asn	missense splice_region	Exon 7 of 8	ENSP00000367104.3
	BFSP1	ENST00000377868.6	TSL:1	c.667G>A	p.Asp223Asn	missense splice_region	Exon 7 of 8	ENSP00000367099.2
	BFSP1	ENST00000536626.7	TSL:2	c.625G>A	p.Asp209Asn	missense splice_region	Exon 8 of 9	ENSP00000442522.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 137328 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380730 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 680922

African (AFR) AF: 0.00 AC: 0 AN: 30312

American (AMR) AF: 0.00 AC: 0 AN: 30376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24740

East Asian (EAS) AF: 0.00 AC: 0 AN: 34570

South Asian (SAS) AF: 0.00 AC: 0 AN: 75258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073408

Other (OTH) AF: 0.0000175 AC: 1 AN: 57278

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 33 Pathogenic:1

May 09, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.62		Gain of MoRF binding (P = 0.0311)
MVP		0.98
MPC		0.39
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.33
gMVP		0.45
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
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

Other links and lift over

dbSNP: rs1085307126; hg19: chr20-17477583;