Variant 3-180971083-GA-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005087.4(FXR1):c.1603+733delA variant causes a intron change. The variant allele was found at a frequency of 0.0000488 in 1,229,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

FXR1
NM_005087.4 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.22

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
FXR1	NM_005087.4 linkuse as main transcript	c.1603+733delA	intron_variant	ENST00000357559.9	NP_005078.2	P51114-1
FXR1	NM_001013438.3 linkuse as main transcript	c.1603+733delA	intron_variant		NP_001013456.1	P51114-2
FXR1	NM_001013439.3 linkuse as main transcript	c.1348+733delA	intron_variant		NP_001013457.1	P51114-3
FXR1	NM_001363882.1 linkuse as main transcript	c.1348+733delA	intron_variant		NP_001350811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXR1	ENST00000357559.9 linkuse as main transcript	c.1603+733delA		intron_variant		1	NM_005087.4	ENSP00000350170.3		P51114-1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1077710

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

527662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000442

Gnomad4 AMR exome

AF:

0.000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000256

Gnomad4 SAS exome

AF:

0.0000147

Gnomad4 FIN exome

AF:

0.0000868

Gnomad4 NFE exome

AF:

0.0000430

Gnomad4 OTH exome

AF:

0.000129

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151556

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73978

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myopathy, congenital proximal, with minicore lesions

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 16, 2024

- -

Multiminicore myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 28, 2020

The homozygous p.Lys569AsnfsTer57 variant in FXR1 was identified by our study in 3 siblings with multiminicore myopathy (PMID: 30770808). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 569 and leads to a premature termination codon 57 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While there is some evidence to suggest that loss of function of the FXR1 gene is a disease mechanism in autosomal recessive multiminicore myopathy, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). Furthermore, although this gene has been reported in association with multiminicore myopathy, it currently has moderate evidence for these associations. In summary, the clinical significance of the p.Lys569AsnfsTer57 variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_Supporting, PP1 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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