rs25731

Variant names:

• chrX-147925702-T-A
• rs25731
• NM_002024.6:c.198+69T>A

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.198+69T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 702,548 control chromosomes in the GnomAD database, including 5,214 homozygotes. There are 22,042 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (688 hom., 2698 hem., cov: 23)
  • Exomes 𝑓: 0.10 (4526 hom. 19344 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.481
• 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=-0.81).
• BP6: Variant X-147925702-T-A is Benign according to our data. Variant chrX-147925702-T-A is described in ClinVar as Benign. ClinVar VariationId is 1179613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.198+69T>A		intron_variant	Intron 3 of 16	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.198+69T>A		intron_variant	Intron 3 of 16	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 9141 AN: 111344 Hom.: 690 Cov.: 23

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0630

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.100 AC: 59107 AN: 591152 Hom.: 4526 AF XY: 0.111 AC XY: 19344 AN XY: 175018

African (AFR) AF: 0.0129 AC: 214 AN: 16600

American (AMR) AF: 0.269 AC: 8828 AN: 32810

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 886 AN: 16052

East Asian (EAS) AF: 0.529 AC: 14354 AN: 27143

South Asian (SAS) AF: 0.112 AC: 4810 AN: 42970

European-Finnish (FIN) AF: 0.0618 AC: 2433 AN: 39360

Middle Eastern (MID) AF: 0.0946 AC: 218 AN: 2305

European-Non Finnish (NFE) AF: 0.0630 AC: 24231 AN: 384919

Other (OTH) AF: 0.108 AC: 3133 AN: 28993

GnomAD4 genome AF: 0.0820 AC: 9139 AN: 111396 Hom.: 688 Cov.: 23 AF XY: 0.0803 AC XY: 2698 AN XY: 33612

African (AFR) AF: 0.0161 AC: 494 AN: 30726

American (AMR) AF: 0.209 AC: 2184 AN: 10453

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 154 AN: 2633

East Asian (EAS) AF: 0.567 AC: 1946 AN: 3430

South Asian (SAS) AF: 0.102 AC: 271 AN: 2647

European-Finnish (FIN) AF: 0.0503 AC: 301 AN: 5990

Middle Eastern (MID) AF: 0.0642 AC: 14 AN: 218

European-Non Finnish (NFE) AF: 0.0652 AC: 3464 AN: 53098

Other (OTH) AF: 0.123 AC: 186 AN: 1518

Alfa AF: 0.0702 Hom.: 388

Bravo AF: 0.102

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

- -

Jun 18, 2021

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	-0.81
CADD	Benign	0.65
DANN	Benign	0.74
PhyloP100		-0.48
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: rs25731; hg19: chrX-147007220;