X-147937021-G-T

Variant names:

• chrX-147937021-G-T
• rs5904650
• NM_002024.6:c.990+408G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002024.6(FMR1):​c.990+408G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 1.0 (38909 hom., 33086 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 1 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: Orphanet, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• fragile X-associated tremor/ataxia syndrome

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

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.990+408G>T		intron	N/A	NP_002015.1
	FMR1	NM_001185076.2		c.990+408G>T		intron	N/A	NP_001172005.1
	FMR1	NM_001185082.2		c.990+408G>T		intron	N/A	NP_001172011.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.990+408G>T		intron	N/A	ENSP00000359506.5
	FMR1	ENST00000218200.12	TSL:1	c.990+408G>T		intron	N/A	ENSP00000218200.8
	FMR1	ENST00000439526.6	TSL:1	c.984+408G>T		intron	N/A	ENSP00000395923.2

Frequencies

GnomAD3 genomes AF: 1.00 AC: 110857 AN: 110857 Hom.: 38914 Cov.: 23

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 1.00 AC: 110904 AN: 110904 Hom.: 38909 Cov.: 23 AF XY: 1.00 AC XY: 33086 AN XY: 33086

African (AFR) AF: 1.00 AC: 30539 AN: 30539

American (AMR) AF: 1.00 AC: 10395 AN: 10395

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2634 AN: 2634

East Asian (EAS) AF: 1.00 AC: 3520 AN: 3520

South Asian (SAS) AF: 1.00 AC: 2635 AN: 2635

European-Finnish (FIN) AF: 1.00 AC: 5891 AN: 5891

Middle Eastern (MID) AF: 1.00 AC: 215 AN: 215

European-Non Finnish (NFE) AF: 1.00 AC: 52871 AN: 52871

Other (OTH) AF: 1.00 AC: 1519 AN: 1519

Alfa AF: 1.00 Hom.: 9259

Bravo AF: 1.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.4
DANN	Benign	0.65
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs5904650; hg19: chrX-147018540;