NM_005087.4:c.1603+733dupA

Variant names:

• chr3-180971083-G-GA
• rs769011065
• NM_005087.4:c.1603+733dupA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_005087.4(FXR1):​c.1603+733dupA variant causes a intron 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).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: FXR1 NM_005087.4 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.22
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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_005087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	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

Sel.	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: 5 AN: 151556 Hom.: 0 Cov.: 31

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: 20 AN: 108874 AF XY: 0.000216

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.: 0 Cov.: 20 AF XY: 0.000131 AC XY: 69 AN XY: 527534

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

African (AFR) AF: 0.000132 AC: 3 AN: 22658

American (AMR) AF: 0.000265 AC: 6 AN: 22622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14488

East Asian (EAS) AF: 0.0000854 AC: 1 AN: 11708

South Asian (SAS) AF: 0.000249 AC: 17 AN: 68170

European-Finnish (FIN) AF: 0.0000867 AC: 1 AN: 11530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.000111 AC: 98 AN: 883488

Other (OTH) AF: 0.0000777 AC: 3 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.

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151556 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73978

African (AFR) AF: 0.00 AC: 0 AN: 41244

American (AMR) AF: 0.0000658 AC: 1 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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

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

Other links and lift over

dbSNP: rs769011065; hg19: chr3-180688871;