rs25731

Positions:

• chrX-147925702-T-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
FMR1	NM_002024.6	c.198+69T>A		intron_variant		ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.198+69T>A		intron_variant		1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 9141 AN: 111344 Hom.: 690 Cov.: 23 AF XY: 0.0804 AC XY: 2699 AN XY: 33550

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

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.0552

Gnomad4 EAS exome AF: 0.529

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0618

Gnomad4 NFE exome AF: 0.0630

Gnomad4 OTH exome AF: 0.108

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

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.0585

Gnomad4 EAS AF: 0.567

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0652

Gnomad4 OTH AF: 0.123

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.65
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs25731; hg19: chrX-147007220;