rs25726

Variant names:

• chrX-147921821-A-G
• rs25726
• NM_002024.6:c.52-112A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002024.6(FMR1):​c.52-112A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 504,986 control chromosomes in the GnomAD database, including 3,346 homozygotes. There are 22,788 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (720 hom., 4022 hem., cov: 23)
  • Exomes 𝑓: 0.14 (2626 hom. 18766 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0640
• Publications: 3 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: Orphanet, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• fragile X-associated tremor/ataxia syndrome

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

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-147921821-A-G is Benign according to our data. Variant chrX-147921821-A-G is described in ClinVar as Benign. ClinVar VariationId is 1224679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.52-112A>G		intron_variant	Intron 1 of 16	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.52-112A>G		intron_variant	Intron 1 of 16	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 14096 AN: 111665 Hom.: 718 Cov.: 23

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0870

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00499

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.129

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.138 AC: 54454 AN: 393269 Hom.: 2626 AF XY: 0.147 AC XY: 18766 AN XY: 127999

African (AFR) AF: 0.102 AC: 1133 AN: 11092

American (AMR) AF: 0.0823 AC: 1632 AN: 19833

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 1840 AN: 12485

East Asian (EAS) AF: 0.0125 AC: 301 AN: 24080

South Asian (SAS) AF: 0.179 AC: 5752 AN: 32155

European-Finnish (FIN) AF: 0.150 AC: 5326 AN: 35414

Middle Eastern (MID) AF: 0.132 AC: 311 AN: 2352

European-Non Finnish (NFE) AF: 0.151 AC: 35331 AN: 234147

Other (OTH) AF: 0.130 AC: 2828 AN: 21711

GnomAD4 genome AF: 0.126 AC: 14105 AN: 111717 Hom.: 720 Cov.: 23 AF XY: 0.118 AC XY: 4022 AN XY: 33949

African (AFR) AF: 0.104 AC: 3203 AN: 30846

American (AMR) AF: 0.0865 AC: 913 AN: 10552

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 345 AN: 2642

East Asian (EAS) AF: 0.00501 AC: 18 AN: 3596

South Asian (SAS) AF: 0.152 AC: 412 AN: 2716

European-Finnish (FIN) AF: 0.144 AC: 857 AN: 5960

Middle Eastern (MID) AF: 0.132 AC: 28 AN: 212

European-Non Finnish (NFE) AF: 0.152 AC: 8050 AN: 52988

Other (OTH) AF: 0.117 AC: 179 AN: 1524

Alfa AF: 0.138 Hom.: 830

Bravo AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.59
PhyloP100		0.064
Mutation Taster		=100/0	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: rs25726; hg19: chrX-147003339;