rs143611778

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.746

Publications

1 publications found

Variant links:

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

FMR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.375T>C	p.Thr125Thr	synonymous_variant	Exon 5 of 17	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9 link	c.375T>C	p.Thr125Thr	synonymous_variant	Exon 5 of 17	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes

AF:

0.000536

AC:

AN:

111987

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000885

AC XY:

321

AN XY:

362827

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26373

American (AMR)

AF:

0.000710

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.000568

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30161

South Asian (SAS)

AF:

0.000333

AC:

AN:

54104

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00105

AC:

880

AN:

841391

Other (OTH)

AF:

0.000738

AC:

AN:

46072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000536

AC:

AN:

112041

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

34207

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30862

American (AMR)

AF:

0.00104

AC:

AN:

10570

Ashkenazi Jewish (ASJ)

AF:

0.000377

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.000372

AC:

AN:

2691

European-Finnish (FIN)

AF:

0.000165

AC:

AN:

6079

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000771

AC:

AN:

53185

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000982

Hom.:

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

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 05, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2016

Eurofins Ntd Llc (ga)

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.0

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over