Genetic Variant NM_001105079.3:c.1616C>T (chr16-30665313-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001105079.3(FBRS):c.1616C>T(p.Thr539Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,561,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FBRS
NM_001105079.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

FBRS (HGNC:20442): (fibrosin) Fibrosin is a lymphokine secreted by activated lymphocytes that induces fibroblast proliferation (Prakash and Robbins, 1998 [PubMed 9809749]).[supplied by OMIM, Mar 2008]

FBRS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06687158).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRS	NM_001105079.3 link	c.1616C>T	p.Thr539Met	missense_variant	Exon 10 of 18	ENST00000356166.11	NP_001098549.2	Q9HAH7J3KNZ9B3KTZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBRS	ENST00000356166.11 link	c.1616C>T	p.Thr539Met	missense_variant	Exon 10 of 18	5	NM_001105079.3	ENSP00000348489.5	J3KNZ9
FBRS	ENST00000287468.5 link	c.56C>T	p.Thr19Met	missense_variant	Exon 4 of 12	5		ENSP00000287468.5	Q9HAH7-2
FBRS	ENST00000543786.5 link	n.585-1606C>T		intron_variant	Intron 4 of 9	2		ENSP00000456204.1	H3BRE6

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000182

AC:

AN:

164564

Hom.:

AF XY:

0.0000336

AC XY:

AN XY:

89216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000303

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1409560

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

696668

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000157

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000857

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.T19M) alteration is located in exon 4 (coding exon 3) of the FBRS gene. This alteration results from a C to T substitution at nucleotide position 56, causing the threonine (T) at amino acid position 19 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.0076

.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.090

Sift

Benign

0.090

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.0010

.;B

Vest4

0.14

MutPred

0.30

.;Loss of glycosylation at T19 (P = 0.0168);

MVP

0.043

MPC

0.38

ClinPred

0.11

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 18

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over