X-147928763-T-C

Variant names:

• chrX-147928763-T-C
• rs143611778
• NM_002024.6:c.375T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002024.6(FMR1):​c.375T>C​(p.Thr125Thr) 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 NM_002024.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.746
• Publications: 1 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 -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 VariationId is 286418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002024.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 17	NP_002015.1
	FMR1	NM_001185076.2		c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 16	NP_001172005.1
	FMR1	NM_001185082.2		c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 16	NP_001172011.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 17	ENSP00000359506.5
	FMR1	ENST00000218200.12	TSL:1	c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 16	ENSP00000218200.8
	FMR1	ENST00000439526.6	TSL:1	c.375T>C	p.Thr125Thr	synonymous	Exon 5 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 60 AN: 111987 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000590 AC: 108 AN: 183138 AF XY: 0.000591

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 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

African (AFR) AF: 0.0000379 AC: 1 AN: 26373

American (AMR) AF: 0.000710 AC: 25 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.000568 AC: 11 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.000333 AC: 18 AN: 54104

European-Finnish (FIN) AF: 0.000568 AC: 23 AN: 40528

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.00105 AC: 880 AN: 841391

Other (OTH) AF: 0.000738 AC: 34 AN: 46072

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

African (AFR) AF: 0.000162 AC: 5 AN: 30862

American (AMR) AF: 0.00104 AC: 11 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2691

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000771 AC: 41 AN: 53185

Other (OTH) AF: 0.00 AC: 0 AN: 1524

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

Apr 13, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jun 14, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.70
PhyloP100		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs143611778; hg19: chrX-147010281;