dbSNP rs29282: FMR1:c.630+841T>C (chrX-147931085-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002024.6(FMR1):c.630+841T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0822 in 111,445 control chromosomes in the GnomAD database, including 318 homozygotes. There are 2,544 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.082 ( 318 hom., 2543 hem., cov: 22)

Exomes 𝑓: 0.11 ( 0 hom. 1 hem. )

Consequence

FMR1
NM_002024.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.683

Publications

3 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6 link	c.630+841T>C		intron_variant	Intron 7 of 16	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.630+841T>C		intron_variant	Intron 7 of 16	1	NM_002024.6	ENSP00000359506.5		Q06787-1

Frequencies

GnomAD3 genomes

AF:

0.0822

AC:

9156

AN:

111371

Hom.:

319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0999

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.000841

Gnomad SAS

AF:

0.0259

Gnomad FIN

AF:

0.0936

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0846

Gnomad OTH

AF:

0.0744

GnomAD4 exome

AF:

0.111

AC:

AN:

Hom.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

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

GnomAD4 genome

AF:

0.0822

AC:

9156

AN:

111427

Hom.:

318

Cov.:

AF XY:

0.0755

AC XY:

2543

AN XY:

33677

show subpopulations

African (AFR)

AF:

0.0999

AC:

3069

AN:

30718

American (AMR)

AF:

0.0550

AC:

577

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

168

AN:

2649

East Asian (EAS)

AF:

0.000844

AC:

AN:

3556

South Asian (SAS)

AF:

0.0260

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.0936

AC:

562

AN:

6004

Middle Eastern (MID)

AF:

0.0826

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0846

AC:

4474

AN:

52912

Other (OTH)

AF:

0.0735

AC:

111

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

311

622

933

1244

1555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0825

Hom.:

1109

Bravo

AF:

0.0825

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

6.8

(source)

DANN

Benign

0.46

PhyloP100

-0.68

Mutation Taster

=100/0

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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rs29282

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over