dbSNP rs555665082: FBRSL1:p.Arg71His (chr12-132490782-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001367871.1(FBRSL1):c.212G>A(p.Arg71His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,229,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

FBRSL1
NM_001367871.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

Publications

0 publications found

Variant links:

Genes affected

FBRSL1 (HGNC:29308): (fibrosin like 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

FBRSL1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
syndromic complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Broad Center for Mendelian Genomics

FBRSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013398141).

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 19	ENST00000680143.1	NP_001354800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBRSL1	ENST00000680143.1 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1	A0A7P0Z485
FBRSL1	ENST00000434748.2 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 17	1		ENSP00000396160.2	Q9HCM7
FBRSL1	ENST00000650108.1 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 20			ENSP00000496901.1	A0A3B3IRR3

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

150628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000592

AC:

AN:

33756

AF XY:

0.0000478

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.000482

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:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1078636

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

516722

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

21514

American (AMR)

AF:

0.000117

AC:

AN:

8578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14486

East Asian (EAS)

AF:

0.00

AC:

AN:

22826

South Asian (SAS)

AF:

0.00

AC:

AN:

28598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21242

Middle Eastern (MID)

AF:

0.000279

AC:

AN:

3588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

916272

Other (OTH)

AF:

0.0000722

AC:

AN:

41532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000199

AC:

AN:

150736

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

73668

show subpopulations

African (AFR)

AF:

0.000701

AC:

AN:

41344

American (AMR)

AF:

0.0000660

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67640

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.000106

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.212G>A (p.R71H) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a G to A substitution at nucleotide position 212, causing the arginine (R) at amino acid position 71 to be replaced by a histidine (H). 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

Pathogenic

0.79

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;.

PhyloP100

1.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.060

T;.

Polyphen

1.0

D;.

Vest4

0.20

MutPred

0.24

Loss of MoRF binding (P = 0.0615);Loss of MoRF binding (P = 0.0615);

MVP

0.061

ClinPred

0.099

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.14

gMVP

0.25

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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rs555665082

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over