rs1555799947

Variant names:

• chr20-17494135-A-TT
• rs1555799947
• NM_001195.5:c.1937delTinsAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001195.5(BFSP1):​c.1937delTinsAA​(p.Val646GlufsTer29) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V646M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BFSP1 NM_001195.5 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0305 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.1937delTinsAA	p.Val646GlufsTer29	frameshift missense	Exon 8 of 8	NP_001186.1
	BFSP1	NM_001424338.1		c.1829delTinsAA	p.Val610GlufsTer29	frameshift missense	Exon 7 of 7	NP_001411267.1
	BFSP1	NM_001278607.2		c.1604delTinsAA	p.Val535GlufsTer29	frameshift missense	Exon 8 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.1937delTinsAA	p.Val646GlufsTer29	frameshift missense	Exon 8 of 8	ENSP00000367104.3
	BFSP1	ENST00000377868.6	TSL:1	c.1562delTinsAA	p.Val521GlufsTer29	frameshift missense	Exon 8 of 8	ENSP00000367099.2
	BFSP1	ENST00000536626.7	TSL:2	c.1520delTinsAA	p.Val507GlufsTer29	frameshift missense	Exon 9 of 9	ENSP00000442522.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cataract 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

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

Other links and lift over

dbSNP: rs1555799947; hg19: chr20-17474780;