X-147929940-A-T

Variant names:

• chrX-147929940-A-T
• rs886041088
• NM_002024.6:c.420-8A>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.420-8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,049,043 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FMR1 NM_002024.6 splice_region, intron
• Scores: Splicing: ADA: 0.000007064
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.420-8A>T		splice_region intron	N/A	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.420-8A>T		splice_region intron	N/A	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.420-8A>T		splice_region 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.420-8A>T		splice_region intron	N/A	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.420-8A>T		splice_region intron	N/A	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.420-8A>T		splice_region intron	N/A	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 110828 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.0000424 AC: 7 AN: 164996 AF XY: 0.00

Gnomad AFR exome AF: 0.0000843

Gnomad AMR exome AF: 0.0000391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000693

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 11 AN: 1049043 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 325985

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

African (AFR) AF: 0.00 AC: 0 AN: 25001

American (AMR) AF: 0.0000891 AC: 3 AN: 33685

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18811

East Asian (EAS) AF: 0.00 AC: 0 AN: 29883

South Asian (SAS) AF: 0.00 AC: 0 AN: 51265

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3433

European-Non Finnish (NFE) AF: 0.00000997 AC: 8 AN: 802589

Other (OTH) AF: 0.00 AC: 0 AN: 44187

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 110828 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33174

African (AFR) AF: 0.00 AC: 0 AN: 30486

American (AMR) AF: 0.00 AC: 0 AN: 10415

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5833

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52845

Other (OTH) AF: 0.00 AC: 0 AN: 1485

Alfa AF: 0.00385 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.28
DANN	Benign	0.50
PhyloP100		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0040
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: rs886041088; hg19: chrX-147011459;