chrX-147928320-A-G

Variant names:

• chrX-147928320-A-G
• rs1057518850
• NM_002024.6:c.199-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_002024.6(FMR1):​c.199-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FMR1 NM_002024.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.96
• 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 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.037914693 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of 11, new splice context is: tttgtgtgggtgtattccAGagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-147928320-A-G is Pathogenic according to our data. Variant chrX-147928320-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374035.Status of the report is criteria_provided_single_submitter, 1 stars.

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.199-2A>G		splice_acceptor intron	N/A	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.199-2A>G		splice_acceptor intron	N/A	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.199-2A>G		splice_acceptor 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.199-2A>G		splice_acceptor intron	N/A	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.199-2A>G		splice_acceptor intron	N/A	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.199-2A>G		splice_acceptor intron	N/A	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080727 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 348055

African (AFR) AF: 0.00 AC: 0 AN: 26084

American (AMR) AF: 0.00 AC: 0 AN: 35151

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19246

East Asian (EAS) AF: 0.00 AC: 0 AN: 30068

South Asian (SAS) AF: 0.00 AC: 0 AN: 53589

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4011

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826558

Other (OTH) AF: 0.00 AC: 0 AN: 45511

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autistic behavior;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	0.98
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.0
GERP RS		4.2
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.82		Position offset: 2

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

Other links and lift over

dbSNP: rs1057518850; hg19: chrX-147009838;