rs25726

Positions:

• chrX-147921821-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000370475.9(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 ENST00000370475.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0640

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
FMR1	NM_002024.6	c.52-112A>G		intron_variant		ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.52-112A>G		intron_variant		1	NM_002024.6	ENSP00000359506	P3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 14096 AN: 111665 Hom.: 718 Cov.: 23 AF XY: 0.118 AC XY: 4008 AN XY: 33887

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

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0125

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.130

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

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0865

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.117

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.59

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: rs25726; hg19: chrX-147003339;