NM_003571.4:c.954G>T

Variant names:

• chr3-133466890-G-T
• rs146972354
• NM_003571.4:c.954G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003571.4(BFSP2):​c.954G>T​(p.Arg318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,613,946 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: BFSP2 NM_003571.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.165
• Publications: 2 publications found

Genes affected

BFSP2 (HGNC:1041): (beaded filament structural protein 2) More than 99% of the vertebrate ocular lens is comprised of terminally differentiated lens fiber cells. Two lens-specific intermediate filament-like proteins, the protein product of this gene (phakinin), and filensin, are expressed only after fiber cell differentiation has begun. Both proteins are found in a structurally unique cytoskeletal element that is referred to as the beaded filament (BF). Mutations in this gene have been associated with juvenile-onset, progressive cataracts and Dowling-Meara epidermolysis bullosa simplex. [provided by RefSeq, Jun 2009]

BFSP2-AS1 (HGNC:28425): (BFSP2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016733706).
• BP6: Variant 3-133466890-G-T is Benign according to our data. Variant chr3-133466890-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 474094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003571.4. 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
	BFSP2	NM_003571.4	MANE Select	c.954G>T	p.Arg318Ser	missense	Exon 5 of 7	NP_003562.1
	BFSP2-AS1	NR_135276.2		n.209-11427C>A		intron	N/A
	BFSP2-AS1	NR_135277.2		n.209-11427C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BFSP2	ENST00000302334.3	TSL:1 MANE Select	c.954G>T	p.Arg318Ser	missense	Exon 5 of 7	ENSP00000304987.2
	BFSP2	ENST00000510039.1	TSL:3	n.99G>T		non_coding_transcript_exon	Exon 2 of 4
	BFSP2	ENST00000511434.1	TSL:3	n.420G>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152010 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.000378 AC: 95 AN: 251454 AF XY: 0.000235

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.000347

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: 0.000326

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1461818 Hom.: 1 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 727204

African (AFR) AF: 0.00585 AC: 196 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111974

Other (OTH) AF: 0.000315 AC: 19 AN: 60390

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152128 Hom.: 2 Cov.: 30 AF XY: 0.00156 AC XY: 116 AN XY: 74384

African (AFR) AF: 0.00549 AC: 228 AN: 41498

American (AMR) AF: 0.00151 AC: 23 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.000648 Hom.: 1

Bravo AF: 0.00185

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 12 multiple types Benign:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.17
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.43
Sift	Benign	0.19	T
Sift4G	Benign	0.080	T
Polyphen		0.046	B
Vest4		0.29
MutPred		0.73		Gain of phosphorylation at R318 (P = 0.1328)
MVP		0.76
MPC		0.18
ClinPred		0.026	T
GERP RS		-1.6
Varity_R		0.23
gMVP		0.60
Mutation Taster		=81/19	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: rs146972354; hg19: chr3-133185734;