NM_002024.6:c.-129_-100dupCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG

Variant names:

• chrX-147912049-C-CGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG
• rs193922936
• NM_002024.6:c.-129_-100dupCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002024.6(FMR1):​c.-129_-100dupCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (10 hom., 114 hem., cov: 2)
  • Exomes 𝑓: 0.00047 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: FMR1 NM_002024.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.618
• Publications: 0 publications found

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

ENSG00000274086 (HGNC:):

ACMG classification

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

• BP6: Variant X-147912049-C-CGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG is Benign according to our data. Variant chrX-147912049-C-CGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG is described in ClinVar as Benign. ClinVar VariationId is 761197.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0198 (694/35017) while in subpopulation EAS AF = 0.0511 (29/567). AF 95% confidence interval is 0.0366. There are 10 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 2. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.-129_-100dupCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 17	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.-129_-100dupCGGCGGCGGCGGCGGCGGCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 17	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 693 AN: 35019 Hom.: 10 Cov.: 2

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.0226

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0122

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00240

Gnomad MID AF: 0.0580

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0237

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000474 AC: 3 AN: 6328 Hom.: 0 Cov.: 0 AF XY: 0.000293 AC XY: 1 AN XY: 3418

African (AFR) AF: 0.00 AC: 0 AN: 33

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 33

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 97

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3

European-Non Finnish (NFE) AF: 0.000337 AC: 2 AN: 5935

Other (OTH) AF: 0.00578 AC: 1 AN: 173

GnomAD4 genome AF: 0.0198 AC: 694 AN: 35017 Hom.: 10 Cov.: 2 AF XY: 0.0197 AC XY: 114 AN XY: 5799

African (AFR) AF: 0.0288 AC: 280 AN: 9714

American (AMR) AF: 0.0218 AC: 60 AN: 2750

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 10 AN: 820

East Asian (EAS) AF: 0.0511 AC: 29 AN: 567

South Asian (SAS) AF: 0.0235 AC: 10 AN: 425

European-Finnish (FIN) AF: 0.00240 AC: 2 AN: 835

Middle Eastern (MID) AF: 0.0690 AC: 4 AN: 58

European-Non Finnish (NFE) AF: 0.0148 AC: 284 AN: 19204

Other (OTH) AF: 0.0236 AC: 11 AN: 467

Alfa AF: 0.00 Hom.: 89

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62

Splicing

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

Other links and lift over

dbSNP: rs193922936; hg19: chrX-146993567;