X-147922046-C-T

Variant names:

• chrX-147922046-C-T
• rs1270092
• NM_002024.6:c.104+61C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002024.6(FMR1):​c.104+61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 112,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 5 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 Gene-Disease associations (from GenCC):

• fragile X syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• fragile X-associated tremor/ataxia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• symptomatic form of fragile X syndrome in female carrier

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS2: High Hemizygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.104+61C>T		intron	N/A	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.104+61C>T		intron	N/A	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.104+61C>T		intron	N/A	NP_001172011.1	Q06787-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.104+61C>T		intron	N/A	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.104+61C>T		intron	N/A	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.104+61C>T		intron	N/A	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112036 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 602956 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 168770

African (AFR) AF: 0.00 AC: 0 AN: 16180

American (AMR) AF: 0.00 AC: 0 AN: 28125

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15153

East Asian (EAS) AF: 0.00 AC: 0 AN: 26614

South Asian (SAS) AF: 0.00 AC: 0 AN: 39145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3070

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 407596

Other (OTH) AF: 0.00 AC: 0 AN: 29043

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112036 Hom.: 0 Cov.: 23 AF XY: 0.0000584 AC XY: 2 AN XY: 34242

African (AFR) AF: 0.0000648 AC: 2 AN: 30866

American (AMR) AF: 0.00 AC: 0 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53127

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.069
PhyloP100		-2.2

Splicing

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

Other links and lift over

dbSNP: rs1270092; hg19: chrX-147003564;