rs25707

Variant names:

• chrX-147928802-G-A
• rs25707
• NM_002024.6:c.414G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002024.6(FMR1):​c.414G>A​(p.Arg138Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,206,186 control chromosomes in the GnomAD database, including 3,659 homozygotes. There are 34,800 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (539 hom., 3151 hem., cov: 23)
  • Exomes 𝑓: 0.087 (3120 hom. 31649 hem.)
• Consequence: FMR1 NM_002024.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.27
• Publications: 13 publications found

Genes affected

FMR1 (HGNC:3775): (fragile X messenger ribonucleoprotein 1) The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010]

FMR1 Gene-Disease associations (from GenCC):

• fragile X syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• fragile X-associated tremor/ataxia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• symptomatic form of fragile X syndrome in female carrier

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-147928802-G-A is Benign according to our data. Variant chrX-147928802-G-A is described in ClinVar as Benign. ClinVar VariationId is 94023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002024.6. 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
	FMR1	NM_002024.6	MANE Select	c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 17	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 16	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 16	NP_001172011.1	Q06787-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 17	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 16	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.414G>A	p.Arg138Arg	synonymous	Exon 5 of 16	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.103 AC: 11406 AN: 111212 Hom.: 539 Cov.: 23

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0867

Gnomad OTH AF: 0.0980

GnomAD2 exomes AF: 0.0812 AC: 14853 AN: 182893 AF XY: 0.0820

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.0765

GnomAD4 exome AF: 0.0872 AC: 95437 AN: 1094923 Hom.: 3120 Cov.: 29 AF XY: 0.0877 AC XY: 31649 AN XY: 360693

African (AFR) AF: 0.174 AC: 4568 AN: 26322

American (AMR) AF: 0.0402 AC: 1413 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 949 AN: 19338

East Asian (EAS) AF: 0.000265 AC: 8 AN: 30146

South Asian (SAS) AF: 0.0985 AC: 5320 AN: 54014

European-Finnish (FIN) AF: 0.0892 AC: 3612 AN: 40508

Middle Eastern (MID) AF: 0.116 AC: 477 AN: 4129

European-Non Finnish (NFE) AF: 0.0895 AC: 75105 AN: 839302

Other (OTH) AF: 0.0867 AC: 3985 AN: 45988

GnomAD4 genome AF: 0.103 AC: 11411 AN: 111263 Hom.: 539 Cov.: 23 AF XY: 0.0940 AC XY: 3151 AN XY: 33521

African (AFR) AF: 0.170 AC: 5188 AN: 30535

American (AMR) AF: 0.0507 AC: 534 AN: 10523

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 124 AN: 2641

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3568

South Asian (SAS) AF: 0.104 AC: 277 AN: 2669

European-Finnish (FIN) AF: 0.0840 AC: 502 AN: 5973

Middle Eastern (MID) AF: 0.130 AC: 28 AN: 216

European-Non Finnish (NFE) AF: 0.0867 AC: 4591 AN: 52941

Other (OTH) AF: 0.100 AC: 151 AN: 1510

Alfa AF: 0.0918 Hom.: 2458

Bravo AF: 0.105

EpiCase AF: 0.0968

EpiControl AF: 0.0946

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fragile X syndrome (1)
-	-	1	Fragile X syndrome;C1839780:Fragile X-associated tremor/ataxia syndrome;C4552079:Premature ovarian failure 1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.2
DANN	Benign	0.63
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs25707; hg19: chrX-147010320; COSMIC: COSV54427915; COSMIC: COSV54427915;