Variant 3-180949239-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005087.4(FXR1):c.526G>A(p.Ala176Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,565,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

FXR1
NM_005087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

FXR1 (HGNC:4023): (FMR1 autosomal homolog 1) The protein encoded by this gene is an RNA binding protein that interacts with the functionally-similar proteins FMR1 and FXR2. These proteins shuttle between the nucleus and cytoplasm and associate with polyribosomes, predominantly with the 60S ribosomal subunit. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

FXR1 links:

FXR1 (HGNC:):

FXR1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0586735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXR1	NM_005087.4 linkuse as main transcript	c.526G>A	p.Ala176Thr	missense_variant	7/17	ENST00000357559.9	NP_005078.2	P51114-1
FXR1	NM_001013438.3 linkuse as main transcript	c.526G>A	p.Ala176Thr	missense_variant	7/16		NP_001013456.1	P51114-2
FXR1	NM_001013439.3 linkuse as main transcript	c.271G>A	p.Ala91Thr	missense_variant	8/18		NP_001013457.1	P51114-3
FXR1	NM_001363882.1 linkuse as main transcript	c.271G>A	p.Ala91Thr	missense_variant	8/17		NP_001350811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXR1	ENST00000357559.9 linkuse as main transcript	c.526G>A	p.Ala176Thr	missense_variant	7/17	1	NM_005087.4	ENSP00000350170.3		P51114-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152254

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251414

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135880

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1413604

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

706480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.0000140

Gnomad4 OTH exome

AF:

0.000170

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000108

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2024

The c.526G>A (p.A176T) alteration is located in exon 7 (coding exon 7) of the FXR1 gene. This alteration results from a G to A substitution at nucleotide position 526, causing the alanine (A) at amino acid position 176 to be replaced by a threonine (T). 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

0.089

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

T;.;T;.;.;T;.;.;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.0070

MetaRNN

Benign

0.059

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

.;.;N;.;.;.;N;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.59

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

1.0

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T;T;T;T

Polyphen

0.0030, 0.0010, 0.0020, 0.0040

.;.;B;.;B;B;B;.;B

Vest4

0.23, 0.092, 0.13, 0.091, 0.090, 0.14

MutPred

0.20

.;.;Gain of catalytic residue at A176 (P = 0.0526);.;.;.;Gain of catalytic residue at A176 (P = 0.0526);.;.;

MVP

0.36

MPC

0.97

ClinPred

0.062

GERP RS

4.6

Varity_R

0.065

gMVP

0.49

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

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