Genetic Variant FMR1:p.Ser524Ser (chrX-147944969-C-T) – ACMG Classification: Benign (-21 pts)

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.1572C>T(p.Ser524Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,204,544 control chromosomes in the GnomAD database, including 4 homozygotes. There are 668 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 0.0012 ( 0 hom., 39 hem., cov: 22)

Exomes 𝑓: 0.0017 ( 4 hom. 629 hem. )

Consequence

FMR1
NM_002024.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.707

Publications

2 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 (MetaRNN=0.009594232).

BP6

Variant X-147944969-C-T is Benign according to our data. Variant chrX-147944969-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.707 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (128/109560) while in subpopulation NFE AF = 0.00213 (112/52566). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 39 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMR1	NM_002024.6	MANE Select	c.1572C>T	p.Ser524Ser	synonymous	Exon 15 of 17	NP_002015.1
FMR1	NM_001185075.2		c.1301C>T	p.Ala434Val	missense	Exon 14 of 16	NP_001172004.1
FMR1	NM_001185081.2		c.1238C>T	p.Ala413Val	missense	Exon 13 of 15	NP_001172010.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMR1	ENST00000370475.9	TSL:1 MANE Select	c.1572C>T	p.Ser524Ser	synonymous	Exon 15 of 17	ENSP00000359506.5
FMR1	ENST00000218200.12	TSL:1	c.1509C>T	p.Ser503Ser	synonymous	Exon 14 of 16	ENSP00000218200.8
FMR1	ENST00000439526.6	TSL:1	c.1503C>T	p.Ser501Ser	synonymous	Exon 14 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

128

AN:

109507

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000195

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.000343

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00138

GnomAD2 exomes

AF:

0.000983

AC:

172

AN:

175013

AF XY:

0.000880

show subpopulations

Gnomad AFR exome

AF:

0.0000796

Gnomad AMR exome

AF:

0.000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000320

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.00171

AC:

1873

AN:

1094984

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

629

AN XY:

360620

show subpopulations

African (AFR)

AF:

0.000341

AC:

AN:

26369

American (AMR)

AF:

0.000229

AC:

AN:

34967

Ashkenazi Jewish (ASJ)

AF:

0.0000519

AC:

AN:

19282

East Asian (EAS)

AF:

0.00

AC:

AN:

30158

South Asian (SAS)

AF:

0.0000933

AC:

AN:

53608

European-Finnish (FIN)

AF:

0.000545

AC:

AN:

40362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00209

AC:

1760

AN:

840139

Other (OTH)

AF:

0.00148

AC:

AN:

45970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.00117

AC:

128

AN:

109560

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

31896

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

30056

American (AMR)

AF:

0.000195

AC:

AN:

10266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2615

East Asian (EAS)

AF:

0.00

AC:

AN:

3459

South Asian (SAS)

AF:

0.000834

AC:

AN:

2397

European-Finnish (FIN)

AF:

0.000343

AC:

AN:

5831

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00213

AC:

112

AN:

52566

Other (OTH)

AF:

0.00136

AC:

AN:

1474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.00180

Hom.:

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00277

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.000981

AC:

119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 05, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

FMR1-related disorder

Benign:1

Jan 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Inborn genetic diseases

Benign:1

Jun 08, 2016

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.

Fragile X syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.82

PhyloP100

0.71

PROVEAN

Benign

0.48

REVEL

Benign

0.073

Sift

Benign

0.043

Sift4G

Benign

0.24

Vest4

0.097

MVP

0.97

ClinPred

0.015

GERP RS

5.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over