X-147928763-T-C

Position:

• chrX-147928763-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000370475.9(FMR1):​c.375T>C​(p.Thr125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,209,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 338 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.00090 (0 hom. 321 hem.)
• Consequence: FMR1 ENST00000370475.9 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.746

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-147928763-T-C is Benign according to our data. Variant chrX-147928763-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 286418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-147928763-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.746 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000536 (60/112041) while in subpopulation AMR AF= 0.00104 (11/10570). AF 95% confidence interval is 0.000583. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMR1	NM_002024.6	c.375T>C	p.Thr125=	synonymous_variant	5/17	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.375T>C	p.Thr125=	synonymous_variant	5/17	1	NM_002024.6	ENSP00000359506	P3

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 60 AN: 111987 Hom.: 0 Cov.: 23 AF XY: 0.000498 AC XY: 17 AN XY: 34143

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000771

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000590 AC: 108 AN: 183138 Hom.: 0 AF XY: 0.000591 AC XY: 40 AN XY: 67676

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.000535

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000316

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000942

Gnomad OTH exome AF: 0.000886

GnomAD4 exome AF: 0.000905 AC: 993 AN: 1097327 Hom.: 0 Cov.: 29 AF XY: 0.000885 AC XY: 321 AN XY: 362827

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000710

Gnomad4 ASJ exome AF: 0.000568

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000738

GnomAD4 genome AF: 0.000536 AC: 60 AN: 112041 Hom.: 0 Cov.: 23 AF XY: 0.000497 AC XY: 17 AN XY: 34207

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000372

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.000771

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000982 Hom.: 6

Bravo AF: 0.000752

EpiCase AF: 0.000546

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs143611778; hg19: chrX-147010281;