chr12-132490728-C-T

Variant names:

Variant summary

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

The NM_001367871.1(FBRSL1):c.158C>T(p.Pro53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000598 in 986,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P53H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

FBRSL1
NM_001367871.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.187

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=0.11205298).

BS2

High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1 link	c.158C>T	p.Pro53Leu	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.158C>T	p.Pro53Leu	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1	A0A7P0Z485
FBRSL1	ENST00000434748.2 link	c.158C>T	p.Pro53Leu	missense_variant	Exon 1 of 17	1		ENSP00000396160.2	Q9HCM7
FBRSL1	ENST00000650108.1 link	c.158C>T	p.Pro53Leu	missense_variant	Exon 1 of 20			ENSP00000496901.1	A0A3B3IRR3

Frequencies

GnomAD3 genomes

AF:

0.0000205

AC:

AN:

146098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

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

GnomAD4 exome

AF:

0.0000666

AC:

AN:

840468

Hom.:

Cov.:

AF XY:

0.0000720

AC XY:

AN XY:

388936

show subpopulations

African (AFR)

AF:

0.0000628

AC:

AN:

15914

American (AMR)

AF:

0.00

AC:

AN:

1222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5258

East Asian (EAS)

AF:

0.00

AC:

AN:

3944

South Asian (SAS)

AF:

0.00

AC:

AN:

17336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1636

European-Non Finnish (NFE)

AF:

0.0000717

AC:

AN:

766568

Other (OTH)

AF:

0.00

AC:

AN:

27650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000205

AC:

AN:

146098

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

71022

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40726

American (AMR)

AF:

0.00

AC:

AN:

14724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65798

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.158C>T (p.P53L) 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 158, causing the proline (P) at amino acid position 53 to be replaced by a leucine (L). 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

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0064

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.47

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

N;.

PhyloP100

0.19

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.020

Sift

Uncertain

0.023

D;.

Sift4G

Benign

0.13

T;.

Polyphen

0.046

B;.

Vest4

0.19

MutPred

0.24

Gain of MoRF binding (P = 0.0265);Gain of MoRF binding (P = 0.0265);

MVP

0.27

ClinPred

0.17

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.17

Mutation Taster

=98/2

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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chr12-132490728-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