X-147912049-CGCGGCGGCGGCGGCGGCGGCG-CGCGGCGGCG

Variant names:

• chrX-147912049-CGCGGCGGCGGCG-C
• rs193922936
• NM_002024.6:c.-111_-100delCGGCGGCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002024.6(FMR1):​c.-111_-100delCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 41,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 2 hem., cov: 2)
  • Exomes 𝑓: 0.00095 (0 hom. 1 hem.)
• Consequence: FMR1 NM_002024.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-147912049-CGCGGCGGCGGCG-C is Benign according to our data. Variant chrX-147912049-CGCGGCGGCGGCG-C is described in ClinVar as Benign. ClinVar VariationId is 1164648.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.-111_-100delCGGCGGCGGCGG		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.-111_-100delCGGCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 17	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 11 AN: 35174 Hom.: 0 Cov.: 2

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000363

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000949 AC: 6 AN: 6321 Hom.: 0 AF XY: 0.000293 AC XY: 1 AN XY: 3415

African (AFR) AF: 0.0303 AC: 1 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: 0.000843 AC: 5 AN: 5930

Other (OTH) AF: 0.00 AC: 0 AN: 171

GnomAD4 genome AF: 0.000313 AC: 11 AN: 35174 Hom.: 0 Cov.: 2 AF XY: 0.000345 AC XY: 2 AN XY: 5800

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000411 AC: 4 AN: 9740

American (AMR) AF: 0.00 AC: 0 AN: 2760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 832

East Asian (EAS) AF: 0.00 AC: 0 AN: 569

South Asian (SAS) AF: 0.00 AC: 0 AN: 426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 69

European-Non Finnish (NFE) AF: 0.000363 AC: 7 AN: 19298

Other (OTH) AF: 0.00 AC: 0 AN: 465

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000248), which strongly suggests a high chance of mosaicism in these individuals.

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

Apr 22, 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		2.7

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;