20-17496947-C-A

Variant names:

• chr20-17496947-C-A
• rs6080719
• NM_001195.5:c.1033G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195.5(BFSP1):​c.1033G>T​(p.Gly345Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. G345S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BFSP1 NM_001195.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.631
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24416187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BFSP1	NM_001195.5	c.1033G>T	p.Gly345Cys	missense_variant	Exon 7 of 8	ENST00000377873.8	NP_001186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BFSP1	ENST00000377873.8	c.1033G>T	p.Gly345Cys	missense_variant	Exon 7 of 8	1	NM_001195.5	ENSP00000367104.3
BFSP1	ENST00000377868.6	c.658G>T	p.Gly220Cys	missense_variant	Exon 7 of 8	1		ENSP00000367099.2
BFSP1	ENST00000536626.7	c.616G>T	p.Gly206Cys	missense_variant	Exon 8 of 9	2		ENSP00000442522.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383284 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 682416

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30460

American (AMR) AF: 0.00 AC: 0 AN: 31108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24824

East Asian (EAS) AF: 0.00 AC: 0 AN: 34494

South Asian (SAS) AF: 0.00 AC: 0 AN: 75780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074424

Other (OTH) AF: 0.00 AC: 0 AN: 57372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	5.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.9	M;.;.
PhyloP100		-0.63
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;D;D
REVEL	Benign	0.097
Sift	Benign	0.052	T;T;T
Sift4G	Uncertain	0.053	T;.;T
Polyphen		0.95	P;D;.
Vest4		0.24
MutPred		0.27		Loss of glycosylation at S344 (P = 0.0608);.;.;
MVP		0.83
MPC		0.38
ClinPred		0.68	D
GERP RS		-5.0
Varity_R		0.10
gMVP		0.22
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs6080719; hg19: chr20-17477592;