rs16999317

Variant names:

• chr20-17494104-G-T
• rs16999317
• NM_001195.5:c.1968C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-17494104-G-T
• chr20-17494104-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195.5(BFSP1):​c.1968C>A​(p.Asp656Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,652 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D656Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (60 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: BFSP1 NM_001195.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.27
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029643774).
• BP6: Variant 20-17494104-G-T is Benign according to our data. Variant chr20-17494104-G-T is described in ClinVar as Benign. ClinVar VariationId is 702116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0137 (2090/152214) while in subpopulation AFR AF = 0.0484 (2011/41522). AF 95% confidence interval is 0.0467. There are 60 homozygotes in GnomAd4. There are 1010 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR,AD,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BFSP1	NM_001195.5	MANE Select	c.1968C>A	p.Asp656Glu	missense	Exon 8 of 8	NP_001186.1	Q12934-1
	BFSP1	NM_001424338.1		c.1860C>A	p.Asp620Glu	missense	Exon 7 of 7	NP_001411267.1
	BFSP1	NM_001278607.2		c.1635C>A	p.Asp545Glu	missense	Exon 8 of 8	NP_001265536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BFSP1	ENST00000377873.8	TSL:1 MANE Select	c.1968C>A	p.Asp656Glu	missense	Exon 8 of 8	ENSP00000367104.3	Q12934-1
	BFSP1	ENST00000377868.6	TSL:1	c.1593C>A	p.Asp531Glu	missense	Exon 8 of 8	ENSP00000367099.2	Q12934-2
	BFSP1	ENST00000929672.1		c.1860C>A	p.Asp620Glu	missense	Exon 7 of 7	ENSP00000599731.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2092 AN: 152096 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00355 AC: 891 AN: 251010 AF XY: 0.00251

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00131 AC: 1914 AN: 1461438 Hom.: 31 Cov.: 31 AF XY: 0.00113 AC XY: 821 AN XY: 727012

African (AFR) AF: 0.0457 AC: 1529 AN: 33442

American (AMR) AF: 0.00287 AC: 128 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111818

Other (OTH) AF: 0.00298 AC: 180 AN: 60364

GnomAD4 genome AF: 0.0137 AC: 2090 AN: 152214 Hom.: 60 Cov.: 33 AF XY: 0.0136 AC XY: 1010 AN XY: 74416

African (AFR) AF: 0.0484 AC: 2011 AN: 41522

American (AMR) AF: 0.00353 AC: 54 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00561 Hom.: 47

Bravo AF: 0.0148

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00446 AC: 541

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cataract 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.11
Sift	Uncertain	0.029	D
Sift4G	Benign	0.82	T
Polyphen		0.12	B
Vest4		0.21
MutPred		0.052		Gain of MoRF binding (P = 0.1009)
MVP		0.39
MPC		0.068
ClinPred		0.014	T
GERP RS		2.4
Varity_R		0.057
gMVP		0.027
Mutation Taster		=97/3	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: rs16999317; hg19: chr20-17474749;