Genetic Variant FXR1:c.1603+733dupA (chr3-180971083-G-GA) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001441509.1(FXR1):c.1707dupA(p.Pro570ThrfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000109 in 1,228,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FXR1
NM_001441509.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.22

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital myopathy
Inheritance: AR Classification: STRONG Submitted by: G2P
myopathy, congenital, with respiratory insufficiency and bone fractures
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
myopathy, congenital proximal, with minicore lesions
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FXR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 3-180971083-G-GA is Pathogenic according to our data. Variant chr3-180971083-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 2443948.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441509.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FXR1	NM_005087.4	MANE Select	c.1603+733dupA		intron	N/A	NP_005078.2	P51114-1
FXR1	NM_001441509.1		c.1707dupA	p.Pro570ThrfsTer7	frameshift	Exon 15 of 17	NP_001428438.1
FXR1	NM_001441512.1		c.1620dupA	p.Pro541ThrfsTer7	frameshift	Exon 16 of 18	NP_001428441.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FXR1	ENST00000357559.9	TSL:1 MANE Select	c.1603+733dupA		intron	N/A	ENSP00000350170.3	P51114-1
FXR1	ENST00000445140.6	TSL:1	c.1603+733dupA		intron	N/A	ENSP00000388828.2	P51114-2
FXR1	ENST00000963215.1		c.1707dupA	p.Pro570ThrfsTer7	frameshift	Exon 15 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000184

AC:

AN:

108874

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.000193

Gnomad AMR exome

AF:

0.000303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000257

Gnomad FIN exome

AF:

0.000161

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000612

GnomAD4 exome

AF:

0.000120

AC:

129

AN:

1077432

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

527534

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000132

AC:

AN:

22658

American (AMR)

AF:

0.000265

AC:

AN:

22622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14488

East Asian (EAS)

AF:

0.0000854

AC:

AN:

11708

South Asian (SAS)

AF:

0.000249

AC:

AN:

68170

European-Finnish (FIN)

AF:

0.0000867

AC:

AN:

11530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4162

European-Non Finnish (NFE)

AF:

0.000111

AC:

AN:

883488

Other (OTH)

AF:

0.0000777

AC:

AN:

38606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41244

American (AMR)

AF:

0.0000658

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67890

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myopathy, congenital proximal, with minicore lesions (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=65/35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over