Genetic Variant FMR1:c.-117_-100delCGGCGGCGGCGGCGGCGG (chrX-147912049-CGCGGCGGCGGCGGCGGCG-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_002024.6(FMR1):c.-117_-100delCGGCGGCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 6,326 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 2)

Exomes 𝑓: 0.00063 ( 0 hom. 2 hem. )

Consequence

FMR1
NM_002024.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66

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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000632 (4/6326) while in subpopulation NFE AF = 0.000674 (4/5933). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 2 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.-117_-100delCGGCGGCGGCGGCGGCGG	5_prime_UTR	Exon 1 of 17	NP_002015.1
FMR1	NM_001185076.2		c.-117_-100delCGGCGGCGGCGGCGGCGG	5_prime_UTR	Exon 1 of 16	NP_001172005.1
FMR1	NM_001185082.2		c.-117_-100delCGGCGGCGGCGGCGGCGG	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.-117_-100delCGGCGGCGGCGGCGGCGG	5_prime_UTR	Exon 1 of 17	ENSP00000359506.5
FMR1	ENST00000218200.12	TSL:1	c.-117_-100delCGGCGGCGGCGGCGGCGG	5_prime_UTR	Exon 1 of 16	ENSP00000218200.8
FMR1	ENST00000439526.6	TSL:1	c.-117_-100delCGGCGGCGGCGGCGGCGG	5_prime_UTR	Exon 1 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.000632

AC:

AN:

6326

Hom.:

AF XY:

0.000585

AC XY:

AN XY:

3416

show subpopulations

African (AFR)

AF:

0.00

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:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000674

AC:

AN:

5933

Other (OTH)

AF:

0.00

AC:

AN:

173

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

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.7

Splicing

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

Publications

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X-147912049-CGCGGCGGCGGCGGCGGCGGCG-CGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over