Genetic Variant FBRSL1:p.Pro54His (chr12-132490731-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001367871.1(FBRSL1):c.161C>A(p.Pro54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 844,496 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. P54A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

FBRSL1
NM_001367871.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25137854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBRSL1	NM_001367871.1 link	c.161C>A	p.Pro54His	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.161C>A	p.Pro54His	missense_variant	Exon 1 of 19		NM_001367871.1	ENSP00000505341.1	A0A7P0Z485
FBRSL1	ENST00000434748.2 link	c.161C>A	p.Pro54His	missense_variant	Exon 1 of 17	1		ENSP00000396160.2	Q9HCM7
FBRSL1	ENST00000650108.1 link	c.161C>A	p.Pro54His	missense_variant	Exon 1 of 20			ENSP00000496901.1	A0A3B3IRR3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000237

AC:

AN:

844496

Hom.:

Cov.:

AF XY:

0.00000256

AC XY:

AN XY:

391372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15972

American (AMR)

AF:

0.00

AC:

AN:

1288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5306

East Asian (EAS)

AF:

0.00

AC:

AN:

4152

South Asian (SAS)

AF:

0.00

AC:

AN:

17338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1632

European-Non Finnish (NFE)

AF:

0.00000260

AC:

AN:

769738

Other (OTH)

AF:

0.00

AC:

AN:

27880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.161C>A (p.P54H) alteration is located in exon 1 (coding exon 1) of the FBRSL1 gene. This alteration results from a C to A substitution at nucleotide position 161, causing the proline (P) at amino acid position 54 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

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

0.065

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.28

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.052

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.021

D;.

Polyphen

1.0

D;.

Vest4

0.17

MutPred

0.19

Loss of catalytic residue at P53 (P = 0.0144);Loss of catalytic residue at P53 (P = 0.0144);

MVP

0.25

ClinPred

0.64

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.19

Mutation Taster

=92/8

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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chr12-132490731-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over