Genetic Variant FBRSL1:p.Ala27Val (chr12-132490650-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001367871.1(FBRSL1):c.80C>T(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 988,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

FBRSL1
NM_001367871.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0850

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.070878565).

BS2

High AC in GnomAdExome4 at 210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1 link	c.80C>T	p.Ala27Val	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.80C>T	p.Ala27Val	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1	A0A7P0Z485
FBRSL1	ENST00000434748.2 link	c.80C>T	p.Ala27Val	missense_variant	Exon 1 of 17	1		ENSP00000396160.2	Q9HCM7
FBRSL1	ENST00000650108.1 link	c.80C>T	p.Ala27Val	missense_variant	Exon 1 of 20			ENSP00000496901.1	A0A3B3IRR3

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

146206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

5518

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000249

AC:

210

AN:

842178

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

390098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15932

American (AMR)

AF:

0.00

AC:

AN:

2236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5644

East Asian (EAS)

AF:

0.00

AC:

AN:

3738

South Asian (SAS)

AF:

0.00

AC:

AN:

18418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1664

European-Non Finnish (NFE)

AF:

0.000271

AC:

208

AN:

766196

Other (OTH)

AF:

0.0000723

AC:

AN:

27672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000137

AC:

AN:

146206

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

71130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40798

American (AMR)

AF:

0.00

AC:

AN:

14708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65808

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

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

Sep 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.80C>T (p.A27V) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a C to T substitution at nucleotide position 80, causing the alanine (A) at amino acid position 27 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0015

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.50

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;.

PhyloP100

-0.085

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.35

N;.

REVEL

Benign

0.029

Sift

Benign

0.20

T;.

Sift4G

Uncertain

0.050

T;.

Polyphen

0.017

B;.

Vest4

0.084

MutPred

0.24

Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);

MVP

0.014

ClinPred

0.028

GERP RS

-1.7

PromoterAI

0.043

Neutral

(source)

Varity_R

0.036

gMVP

0.21

Mutation Taster

=95/5

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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chr12-132490650-C-T

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