rs782738200

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002024.6(FMR1):c.1580G>A(p.Arg527His) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,204,066 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 5 hem. )

Consequence

FMR1
NM_002024.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.65

Publications

4 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23942086).

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.1580G>A	p.Arg527His	missense_variant	Exon 15 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.1580G>A	p.Arg527His	missense_variant	Exon 15 of 17	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes

AF:

0.00000909

AC:

AN:

109963

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000288

AC:

AN:

173482

AF XY:

0.0000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000183

AC:

AN:

1094103

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

359905

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26350

American (AMR)

AF:

0.00

AC:

AN:

34892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19258

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00

AC:

AN:

53494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

839557

Other (OTH)

AF:

0.0000218

AC:

AN:

45958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00000909

AC:

AN:

109963

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32213

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30092

American (AMR)

AF:

0.00

AC:

AN:

10295

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2624

East Asian (EAS)

AF:

0.00

AC:

AN:

3494

South Asian (SAS)

AF:

0.00

AC:

AN:

2434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52706

Other (OTH)

AF:

0.00

AC:

AN:

1470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 26, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected -

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

Uncertain:1

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.53

M_CAP

Benign

0.023

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

PhyloP100

5.6

PROVEAN

Benign

0.070

REVEL

Benign

0.089

Sift

Uncertain

0.0040

Sift4G

Benign

0.30

Vest4

0.43

MutPred

0.098

Gain of phosphorylation at A437 (P = 0.0285);

MVP

0.89

ClinPred

0.35

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.84

Mutation Taster

=80/20

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over