3-180948769-A-T

Variant names:

• chr3-180948769-A-T
• rs3026195
• NM_005087.4:c.468A>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005087.4(FXR1):​c.468A>T​(p.Ala156Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,584,718 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (14 hom.)
• Consequence: FXR1 NM_005087.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.132
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-180948769-A-T is Benign according to our data. Variant chr3-180948769-A-T is described in ClinVar as Benign. ClinVar VariationId is 713455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000932 (142/152380) while in subpopulation EAS AF = 0.0197 (102/5190). AF 95% confidence interval is 0.0166. There are 2 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.468A>T	p.Ala156Ala	synonymous	Exon 6 of 17	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.468A>T	p.Ala156Ala	synonymous	Exon 6 of 17	NP_001428438.1
	FXR1	NM_001441510.1		c.468A>T	p.Ala156Ala	synonymous	Exon 6 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.468A>T	p.Ala156Ala	synonymous	Exon 6 of 17	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.468A>T	p.Ala156Ala	synonymous	Exon 6 of 16	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.468A>T	p.Ala156Ala	synonymous	Exon 6 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152262 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00182 AC: 455 AN: 250432 AF XY: 0.00180

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000653 AC: 935 AN: 1432338 Hom.: 14 Cov.: 26 AF XY: 0.000623 AC XY: 445 AN XY: 714336

African (AFR) AF: 0.0000912 AC: 3 AN: 32906

American (AMR) AF: 0.0000448 AC: 2 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.0181 AC: 715 AN: 39456

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000737 AC: 8 AN: 1085182

Other (OTH) AF: 0.00310 AC: 184 AN: 59392

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152380 Hom.: 2 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74524

African (AFR) AF: 0.0000962 AC: 4 AN: 41596

American (AMR) AF: 0.00189 AC: 29 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0197 AC: 102 AN: 5190

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000937

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		-0.13
Mutation Taster		=95/5	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: rs3026195; hg19: chr3-180666557; COSMIC: COSV59761715; COSMIC: COSV59761715;