Genetic Variant FMR1:c.-105_-100dupCGGCGG (chrX-147912049-C-CGCGGCG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_002024.6(FMR1):c.-105_-100dupCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.043 ( 28 hom., 326 hem., cov: 2)

Exomes 𝑓: 0.020 ( 4 hom. 82 hem. )

Failed GnomAD Quality Control

Consequence

FMR1
NM_002024.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.618

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 links:

FMR1-AS1 (HGNC:39081): (FMR1 antisense RNA 1)

FMR1-AS1 links:

ENSG00000274086 (HGNC:):

ENSG00000274086 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant X-147912049-C-CGCGGCG is Benign according to our data. Variant chrX-147912049-C-CGCGGCG is described in ClinVar as Benign. ClinVar VariationId is 794273.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

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	Effect	Exon Rank	Protein
FMR1	NM_002024.6	MANE Select	c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 17	NP_002015.1
FMR1	NM_001185076.2		c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 16	NP_001172005.1
FMR1	NM_001185082.2		c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 16	NP_001172011.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FMR1	ENST00000370475.9	TSL:1 MANE Select	c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 17	ENSP00000359506.5
FMR1	ENST00000218200.12	TSL:1	c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 16	ENSP00000218200.8
FMR1	ENST00000439526.6	TSL:1	c.-105_-100dupCGGCGG	5_prime_UTR	Exon 1 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes

AF:

0.0431

AC:

1514

AN:

35122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0337

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.0105

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0526

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0258

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0199

AC:

124

AN:

6223

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

AN XY:

3323

show subpopulations

African (AFR)

AF:

0.0313

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0104

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0201

AC:

117

AN:

5832

Other (OTH)

AF:

0.0289

AC:

AN:

173

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0430

AC:

1511

AN:

35120

Hom.:

Cov.:

AF XY:

0.0562

AC XY:

326

AN XY:

5802

show subpopulations

African (AFR)

AF:

0.0310

AC:

302

AN:

9738

American (AMR)

AF:

0.0336

AC:

AN:

2766

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

832

East Asian (EAS)

AF:

0.0105

AC:

AN:

569

South Asian (SAS)

AF:

0.0188

AC:

AN:

425

European-Finnish (FIN)

AF:

0.0526

AC:

AN:

836

Middle Eastern (MID)

AF:

0.103

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0530

AC:

1021

AN:

19250

Other (OTH)

AF:

0.0257

AC:

AN:

467

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.62

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-147912049-CGCGGCGGCGGCGGCGGCGGCG-CGCGGCGGCGGCGGCGGCGGCGGCGGCG

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

Computational scores

Splicing

Publications

Other links and lift over