chrX-147928802-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002024.6(FMR1):c.414G>A(p.Arg138Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,206,186 control chromosomes in the GnomAD database, including 3,659 homozygotes. There are 34,800 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 539 hom., 3151 hem., cov: 23)

Exomes 𝑓: 0.087 ( 3120 hom. 31649 hem. )

Consequence

FMR1
NM_002024.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.27

Publications

13 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-147928802-G-A is Benign according to our data. Variant chrX-147928802-G-A is described in ClinVar as Benign. ClinVar VariationId is 94023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.414G>A	p.Arg138Arg	synonymous_variant	Exon 5 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.414G>A	p.Arg138Arg	synonymous_variant	Exon 5 of 17	1	NM_002024.6	ENSP00000359506.5		Q06787-1

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

11406

AN:

111212

Hom.:

539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0508

Gnomad ASJ

AF:

0.0470

Gnomad EAS

AF:

0.00112

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0840

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0867

Gnomad OTH

AF:

0.0980

GnomAD2 exomes

AF:

0.0812

AC:

14853

AN:

182893

AF XY:

0.0820

show subpopulations

Gnomad AFR exome

AF:

0.176

Gnomad AMR exome

AF:

0.0377

Gnomad ASJ exome

AF:

0.0479

Gnomad EAS exome

AF:

0.000289

Gnomad FIN exome

AF:

0.0906

Gnomad NFE exome

AF:

0.0908

Gnomad OTH exome

AF:

0.0765

GnomAD4 exome

AF:

0.0872

AC:

95437

AN:

1094923

Hom.:

3120

Cov.:

AF XY:

0.0877

AC XY:

31649

AN XY:

360693

show subpopulations

African (AFR)

AF:

0.174

AC:

4568

AN:

26322

American (AMR)

AF:

0.0402

AC:

1413

AN:

35176

Ashkenazi Jewish (ASJ)

AF:

0.0491

AC:

949

AN:

19338

East Asian (EAS)

AF:

0.000265

AC:

AN:

30146

South Asian (SAS)

AF:

0.0985

AC:

5320

AN:

54014

European-Finnish (FIN)

AF:

0.0892

AC:

3612

AN:

40508

Middle Eastern (MID)

AF:

0.116

AC:

477

AN:

4129

European-Non Finnish (NFE)

AF:

0.0895

AC:

75105

AN:

839302

Other (OTH)

AF:

0.0867

AC:

3985

AN:

45988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2754

5508

8262

11016

13770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2834

5668

8502

11336

14170

<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:

0.103

AC:

11411

AN:

111263

Hom.:

539

Cov.:

AF XY:

0.0940

AC XY:

3151

AN XY:

33521

show subpopulations

African (AFR)

AF:

0.170

AC:

5188

AN:

30535

American (AMR)

AF:

0.0507

AC:

534

AN:

10523

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

124

AN:

2641

East Asian (EAS)

AF:

0.00112

AC:

AN:

3568

South Asian (SAS)

AF:

0.104

AC:

277

AN:

2669

European-Finnish (FIN)

AF:

0.0840

AC:

502

AN:

5973

Middle Eastern (MID)

AF:

0.130

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0867

AC:

4591

AN:

52941

Other (OTH)

AF:

0.100

AC:

151

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

369

738

1108

1477

1846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0918

Hom.:

2458

Bravo

AF:

0.105

EpiCase

AF:

0.0968

EpiControl

AF:

0.0946

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 26, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 13, 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

- -

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

Benign:1

Nov 03, 2021

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.2

(source)

DANN

Benign

0.63

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

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