chr3-180961539-T-C

Variant names:

• chr3-180961539-T-C
• rs1805617
• NM_005087.4:c.1062T>C

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.1062T>C​(p.His354His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,491,916 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: FXR1 NM_005087.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.785
• Publications: 2 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 3-180961539-T-C is Benign according to our data. Variant chr3-180961539-T-C is described in ClinVar as Benign. ClinVar VariationId is 789725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.785 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 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.1062T>C	p.His354His	synonymous	Exon 11 of 17	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.1062T>C	p.His354His	synonymous	Exon 11 of 17	NP_001428438.1
	FXR1	NM_001441510.1		c.1062T>C	p.His354His	synonymous	Exon 11 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.1062T>C	p.His354His	synonymous	Exon 11 of 17	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.1062T>C	p.His354His	synonymous	Exon 11 of 16	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.1062T>C	p.His354His	synonymous	Exon 11 of 17	ENSP00000633274.1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 610 AN: 151908 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00106 AC: 267 AN: 250832 AF XY: 0.000723

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000431 AC: 577 AN: 1339896 Hom.: 5 Cov.: 22 AF XY: 0.000368 AC XY: 248 AN XY: 673770

African (AFR) AF: 0.0149 AC: 466 AN: 31194

American (AMR) AF: 0.000606 AC: 27 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00127 AC: 7 AN: 5524

European-Non Finnish (NFE) AF: 0.0000160 AC: 16 AN: 1001006

Other (OTH) AF: 0.00105 AC: 59 AN: 56182

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152020 Hom.: 4 Cov.: 32 AF XY: 0.00393 AC XY: 292 AN XY: 74332

African (AFR) AF: 0.0138 AC: 574 AN: 41504

American (AMR) AF: 0.00177 AC: 27 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00199 Hom.: 2

Bravo AF: 0.00470

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.1
DANN	Benign	0.61
PhyloP100		0.79
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: rs1805617; hg19: chr3-180679327; COSMIC: COSV59764966;