rs73176330

Variant names:

• chr3-180951420-C-T
• rs73176330
• NM_005087.4:c.753C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005087.4(FXR1):​c.753C>T​(p.Thr251Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,612,652 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (90 hom.)
• Consequence: FXR1 NM_005087.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.76
• Publications: 3 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-180951420-C-T is Benign according to our data. Variant chr3-180951420-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 777377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.753C>T	p.Thr251Thr	synonymous	Exon 8 of 17	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.753C>T	p.Thr251Thr	synonymous	Exon 8 of 17	NP_001428438.1
	FXR1	NM_001441510.1		c.753C>T	p.Thr251Thr	synonymous	Exon 8 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.753C>T	p.Thr251Thr	synonymous	Exon 8 of 17	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.753C>T	p.Thr251Thr	synonymous	Exon 8 of 16	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.753C>T	p.Thr251Thr	synonymous	Exon 8 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes AF: 0.00850 AC: 1292 AN: 152036 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00910

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00868 AC: 2180 AN: 251180 AF XY: 0.00862

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.00884

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00807 AC: 11783 AN: 1460498 Hom.: 90 Cov.: 29 AF XY: 0.00800 AC XY: 5814 AN XY: 726702

African (AFR) AF: 0.000777 AC: 26 AN: 33450

American (AMR) AF: 0.00159 AC: 71 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00440 AC: 379 AN: 86198

European-Finnish (FIN) AF: 0.0387 AC: 2067 AN: 53402

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.00787 AC: 8743 AN: 1110810

Other (OTH) AF: 0.00625 AC: 377 AN: 60350

GnomAD4 genome AF: 0.00849 AC: 1292 AN: 152154 Hom.: 16 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74374

African (AFR) AF: 0.00123 AC: 51 AN: 41514

American (AMR) AF: 0.00412 AC: 63 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.0491 AC: 519 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68008

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00825 Hom.: 9

Bravo AF: 0.00453

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00545

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs73176330; hg19: chr3-180669208; COSMIC: COSV99976765; COSMIC: COSV99976765;