chr3-180948154-G-C

Variant names:

• chr3-180948154-G-C
• rs1805599
• NM_005087.4:c.271-193G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001441509.1(FXR1):​c.271-193G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FXR1 NM_001441509.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXR1	NM_005087.4	MANE Select	c.271-193G>C		intron	N/A	NP_005078.2
	FXR1	NM_001441509.1		c.271-193G>C		intron	N/A	NP_001428438.1
	FXR1	NM_001441510.1		c.271-193G>C		intron	N/A	NP_001428439.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXR1	ENST00000357559.9	TSL:1 MANE Select	c.271-193G>C		intron	N/A	ENSP00000350170.3
	FXR1	ENST00000445140.6	TSL:1	c.271-193G>C		intron	N/A	ENSP00000388828.2
	FXR1	ENST00000963215.1		c.271-193G>C		intron	N/A	ENSP00000633274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 1 AN: 460600 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 242812

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

African (AFR) AF: 0.00 AC: 0 AN: 12456

American (AMR) AF: 0.00 AC: 0 AN: 17074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13574

East Asian (EAS) AF: 0.00 AC: 0 AN: 30972

South Asian (SAS) AF: 0.00 AC: 0 AN: 42656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2028

European-Non Finnish (NFE) AF: 0.00000359 AC: 1 AN: 278666

Other (OTH) AF: 0.00 AC: 0 AN: 26166

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.6
DANN	Benign	0.77
PhyloP100		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1805599; hg19: chr3-180665942;