rs25714

chrX-147936627-C-T

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.990+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,016,839 control chromosomes in the GnomAD database, including 8,332 homozygotes. There are 32,742 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1085 hom., 3999 hem., cov: 23)
  • Exomes 𝑓: 0.10 (7247 hom. 28743 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.190

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=-0.83).
• BP6: Variant X-147936627-C-T is Benign according to our data. Variant chrX-147936627-C-T is described in ClinVar as [Benign]. Clinvar id is 94025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-147936627-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMR1	NM_002024.6	c.990+14C>T		intron_variant		ENST00000370475.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMR1	ENST00000370475.9	c.990+14C>T		intron_variant		1	NM_002024.6	P3

Frequencies

GnomAD3 genomes AF: 0.121 AC: 13402 AN: 110776 Hom.: 1088 Cov.: 23 AF XY: 0.121 AC XY: 3997 AN XY: 33078

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0678

Gnomad NFE AF: 0.0674

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.161 AC: 29106 AN: 181043 Hom.: 3566 AF XY: 0.144 AC XY: 9501 AN XY: 65759

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.714

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.0646

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.102 AC: 92357 AN: 906012 Hom.: 7247 Cov.: 18 AF XY: 0.114 AC XY: 28743 AN XY: 253082

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.0589

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.0655

Gnomad4 NFE exome AF: 0.0673

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.121 AC: 13402 AN: 110827 Hom.: 1085 Cov.: 23 AF XY: 0.121 AC XY: 3999 AN XY: 33139

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.705

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.0544

Gnomad4 NFE AF: 0.0674

Gnomad4 OTH AF: 0.157

Alfa AF: 0.0807 Hom.: 2330

Bravo AF: 0.143

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Fragile X syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 12, 2018

- -

not provided Benign:1

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	-0.83
Cadd	Benign	1.3
Dann	Benign	0.38

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: rs25714; hg19: chrX-147018146; COSMIC: COSV54424142; COSMIC: COSV54424142;