Genetic Variant FMR1:p.Glu75Asp (chrX-147928348-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002024.6(FMR1):c.225G>C(p.Glu75Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E75E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

FMR1
NM_002024.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.416

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.225G>C	p.Glu75Asp	missense_variant	Exon 4 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.225G>C	p.Glu75Asp	missense_variant	Exon 4 of 17	1	NM_002024.6	ENSP00000359506.5		Q06787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094957

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360551

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26338

American (AMR)

AF:

0.00

AC:

AN:

35191

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19358

East Asian (EAS)

AF:

0.00

AC:

AN:

30139

South Asian (SAS)

AF:

0.00

AC:

AN:

53979

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4085

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839367

Other (OTH)

AF:

0.00

AC:

AN:

45985

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.;.;.;T;T;.;D;T;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;.;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.7

.;M;M;M;.;.;.;.;M;.;M

PhyloP100

0.42

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.7

.;D;D;.;D;.;D;D;D;.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.022

.;D;D;.;D;.;D;D;D;.;D

Sift4G

Uncertain

0.041

D;D;D;D;D;T;T;D;D;D;D

Polyphen

0.98, 0.63, 0.87, 0.99

.;.;.;D;.;P;P;P;D;.;.

Vest4

0.61

MutPred

0.72

Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);Loss of ubiquitination at K74 (P = 0.0716);

MVP

0.49

MPC

1.5

ClinPred

0.98

GERP RS

-2.0

Varity_R

0.81

gMVP

0.78

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over