3-180912713-G-C

Variant names:

• chr3-180912713-G-C
• rs1457094206
• NM_005087.4:c.28G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005087.4(FXR1):​c.28G>C​(p.Gly10Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G10C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FXR1 NM_005087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• 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

ENSG00000296167 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

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.28G>C	p.Gly10Arg	missense	Exon 1 of 17	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.28G>C	p.Gly10Arg	missense	Exon 1 of 17	NP_001428438.1
	FXR1	NM_001441510.1		c.28G>C	p.Gly10Arg	missense	Exon 1 of 16	NP_001428439.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXR1	ENST00000357559.9	TSL:1 MANE Select	c.28G>C	p.Gly10Arg	missense	Exon 1 of 17	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.28G>C	p.Gly10Arg	missense	Exon 1 of 16	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.28G>C	p.Gly10Arg	missense	Exon 1 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.0026	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.67	P
Vest4		0.56
MutPred		0.65		Loss of methylation at R9 (P = 0.0401)
MVP		0.74
MPC		2.3
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.70
Mutation Taster		=42/58	disease causing

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: rs1457094206; hg19: chr3-180630501;