Genetic Variant FMR1:c.-102_-100dupCGG (chrX-147912049-C-CGCG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_002024.6(FMR1):c.-102_-100dupCGG 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 0.019 ( 9 hom., 126 hem., cov: 2)

Exomes 𝑓: 0.0049 ( 0 hom. 21 hem. )

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant X-147912049-C-CGCG is Benign according to our data. Variant chrX-147912049-C-CGCG is described in ClinVar as Benign. ClinVar VariationId is 752727.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0194 (680/35117) while in subpopulation AMR AF = 0.0297 (82/2763). AF 95% confidence interval is 0.0245. There are 9 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 2. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

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.-102_-100dupCGG	5_prime_UTR	Exon 1 of 17	NP_002015.1
FMR1	NM_001185076.2		c.-102_-100dupCGG	5_prime_UTR	Exon 1 of 16	NP_001172005.1
FMR1	NM_001185082.2		c.-102_-100dupCGG	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.-102_-100dupCGG	5_prime_UTR	Exon 1 of 17	ENSP00000359506.5
FMR1	ENST00000218200.12	TSL:1	c.-102_-100dupCGG	5_prime_UTR	Exon 1 of 16	ENSP00000218200.8
FMR1	ENST00000439526.6	TSL:1	c.-102_-100dupCGG	5_prime_UTR	Exon 1 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

680

AN:

35119

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.00879

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.00120

Gnomad MID

AF:

0.0290

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0151

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.00493

AC:

AN:

6283

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

AN XY:

3377

show subpopulations

African (AFR)

AF:

0.0606

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:

0.00475

AC:

AN:

5894

Other (OTH)

AF:

0.00

AC:

AN:

171

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.0194

AC:

680

AN:

35117

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

126

AN XY:

5801

show subpopulations

African (AFR)

AF:

0.0177

AC:

172

AN:

9741

American (AMR)

AF:

0.0297

AC:

AN:

2763

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

830

East Asian (EAS)

AF:

0.00879

AC:

AN:

569

South Asian (SAS)

AF:

0.0188

AC:

AN:

425

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

834

Middle Eastern (MID)

AF:

0.0345

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0197

AC:

380

AN:

19251

Other (OTH)

AF:

0.0150

AC:

AN:

467

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00298

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-CGCGGCGGCGGCGGCGGCGGCGGCG

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