rs29281

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002024.6(FMR1):c.433G>T(p.Ala145Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 1,191,575 control chromosomes in the GnomAD database, including 192 homozygotes. There are 1,528 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 103 hom., 727 hem., cov: 22)

Exomes 𝑓: 0.0029 ( 89 hom. 801 hem. )

Consequence

FMR1
NM_002024.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.97

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017594695).

BP6

Variant X-147929961-G-T is Benign according to our data. Variant chrX-147929961-G-T is described in ClinVar as Benign. ClinVar VariationId is 129104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.433G>T	p.Ala145Ser	missense_variant	Exon 6 of 17	ENST00000370475.9	NP_002015.1	Q06787-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9 link	c.433G>T	p.Ala145Ser	missense_variant	Exon 6 of 17	1	NM_002024.6	ENSP00000359506.5		Q06787-1

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

2820

AN:

110893

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00931

Gnomad ASJ

AF:

0.000758

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.000506

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.000208

Gnomad OTH

AF:

0.0188

GnomAD2 exomes

AF:

0.00772

AC:

1396

AN:

180837

AF XY:

0.00445

show subpopulations

Gnomad AFR exome

AF:

0.0911

Gnomad AMR exome

AF:

0.00545

Gnomad ASJ exome

AF:

0.00108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000503

Gnomad NFE exome

AF:

0.000298

Gnomad OTH exome

AF:

0.00404

GnomAD4 exome

AF:

0.00289

AC:

3122

AN:

1080631

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

801

AN XY:

348921

show subpopulations

African (AFR)

AF:

0.0893

AC:

2321

AN:

25997

American (AMR)

AF:

0.00610

AC:

214

AN:

35075

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

19269

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30119

South Asian (SAS)

AF:

0.000392

AC:

AN:

53510

European-Finnish (FIN)

AF:

0.000741

AC:

AN:

40463

Middle Eastern (MID)

AF:

0.00229

AC:

AN:

3931

European-Non Finnish (NFE)

AF:

0.000243

AC:

201

AN:

826805

Other (OTH)

AF:

0.00651

AC:

296

AN:

45462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

103

206

308

411

514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.0255

AC:

2826

AN:

110944

Hom.:

103

Cov.:

AF XY:

0.0219

AC XY:

727

AN XY:

33264

show subpopulations

African (AFR)

AF:

0.0882

AC:

2682

AN:

30406

American (AMR)

AF:

0.00930

AC:

AN:

10432

Ashkenazi Jewish (ASJ)

AF:

0.000758

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3546

South Asian (SAS)

AF:

0.000376

AC:

AN:

2661

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

5930

Middle Eastern (MID)

AF:

0.00913

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

52918

Other (OTH)

AF:

0.0186

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

199

299

398

498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0110

Hom.:

398

Bravo

AF:

0.0303

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0920

AC:

353

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.00850

AC:

1032

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 26, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Fragile X syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fragile X syndrome;C1839780:Fragile X-associated tremor/ataxia syndrome;C4552079:Premature ovarian failure 1

Benign:1

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.0050

T;.;.;.;.;T;T;.;T;T;T;.

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.54

T;T;T;T;T;T;.;T;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

.;N;N;N;.;.;.;.;N;.;.;N

PhyloP100

5.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

2.4

.;N;N;.;N;.;N;N;N;.;.;N

REVEL

Benign

0.15

Sift

Benign

1.0

.;T;T;.;T;.;T;T;T;.;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;.;B;.;B;B;B;B;.;.;.

Vest4

0.11

MVP

0.62

MPC

0.81

ClinPred

0.0020

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.31

Mutation Taster

=99/1

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