NM_005087.4:c.1603+790_1603+793delACAG

Variant names:

• chr3-180971145-TAGAC-T
• rs1577005361
• NM_005087.4:c.1603+790_1603+793delACAG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005087.4(FXR1):​c.1603+790_1603+793delACAG variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000539 in 1,113,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: FXR1 NM_005087.4 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.79
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-180971145-TAGAC-T is Pathogenic according to our data. Variant chr3-180971145-TAGAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 828056.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+790_1603+793delACAG		intron	N/A	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.1764_1767delACAG	p.Arg588SerfsTer37	frameshift	Exon 15 of 17	NP_001428438.1
	FXR1	NM_001441512.1		c.1677_1680delACAG	p.Arg559SerfsTer37	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+790_1603+793delACAG		intron	N/A	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.1603+790_1603+793delACAG		intron	N/A	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.1764_1767delACAG	p.Arg588SerfsTer35	frameshift	Exon 15 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000539 AC: 6 AN: 1113656 Hom.: 0 AF XY: 0.00000732 AC XY: 4 AN XY: 546452

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

African (AFR) AF: 0.0000854 AC: 2 AN: 23430

American (AMR) AF: 0.00 AC: 0 AN: 25206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15336

East Asian (EAS) AF: 0.00 AC: 0 AN: 12634

South Asian (SAS) AF: 0.00 AC: 0 AN: 73856

European-Finnish (FIN) AF: 0.0000784 AC: 1 AN: 12754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4208

European-Non Finnish (NFE) AF: 0.00000331 AC: 3 AN: 905682

Other (OTH) AF: 0.00 AC: 0 AN: 40550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0203910), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Myopathy, congenital, with respiratory insufficiency and bone fractures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1577005361; hg19: chr3-180688933;