3-180933327-C-T

Variant names:

• chr3-180933327-C-T
• rs202081242
• NM_005087.4:c.52-7C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005087.4(FXR1):​c.52-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,524,420 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: FXR1 NM_005087.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005346
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.18
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-180933327-C-T is Benign according to our data. Variant chr3-180933327-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 729241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.52-7C>T		splice_region intron	N/A	NP_005078.2	P51114-1
	FXR1	NM_001441509.1		c.52-7C>T		splice_region intron	N/A	NP_001428438.1
	FXR1	NM_001441510.1		c.52-7C>T		splice_region intron	N/A	NP_001428439.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXR1	ENST00000357559.9	TSL:1 MANE Select	c.52-7C>T		splice_region intron	N/A	ENSP00000350170.3	P51114-1
	FXR1	ENST00000445140.6	TSL:1	c.52-7C>T		splice_region intron	N/A	ENSP00000388828.2	P51114-2
	FXR1	ENST00000963215.1		c.52-7C>T		splice_region intron	N/A	ENSP00000633274.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152150 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00198 AC: 494 AN: 249766 AF XY: 0.00204

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00241 AC: 3309 AN: 1372152 Hom.: 6 Cov.: 23 AF XY: 0.00239 AC XY: 1642 AN XY: 687788

African (AFR) AF: 0.000822 AC: 26 AN: 31642

American (AMR) AF: 0.00287 AC: 127 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 87 AN: 25550

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39174

South Asian (SAS) AF: 0.000155 AC: 13 AN: 83940

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53284

Middle Eastern (MID) AF: 0.00639 AC: 36 AN: 5630

European-Non Finnish (NFE) AF: 0.00276 AC: 2843 AN: 1031186

Other (OTH) AF: 0.00286 AC: 164 AN: 57428

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152268 Hom.: 2 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74444

African (AFR) AF: 0.000987 AC: 41 AN: 41554

American (AMR) AF: 0.00386 AC: 59 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68018

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00297 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Myopathy, congenital, with respiratory insufficiency and bone fractures;C5394193:Myopathy, congenital proximal, with minicore lesions (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.036
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: rs202081242; hg19: chr3-180651115;