rs29285

Variant names:

• chrX-147937967-T-G
• rs29285
• NM_002024.6:c.1126-132T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002024.6(FMR1):​c.1126-132T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00813 in 572,818 control chromosomes in the GnomAD database, including 151 homozygotes. There are 1,218 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 0.026 (108 hom., 782 hem., cov: 23)
  • Exomes 𝑓: 0.0038 (43 hom. 436 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.1126-132T>G		intron_variant	Intron 11 of 16	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.1126-132T>G		intron_variant	Intron 11 of 16	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 2904 AN: 112094 Hom.: 108 Cov.: 23

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.000327

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.0186

GnomAD4 exome AF: 0.00380 AC: 1749 AN: 460671 Hom.: 43 AF XY: 0.00274 AC XY: 436 AN XY: 159069

African (AFR) AF: 0.0882 AC: 1197 AN: 13577

American (AMR) AF: 0.00605 AC: 193 AN: 31921

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 18 AN: 14542

East Asian (EAS) AF: 0.00 AC: 0 AN: 26776

South Asian (SAS) AF: 0.000178 AC: 7 AN: 39341

European-Finnish (FIN) AF: 0.000774 AC: 30 AN: 38767

Middle Eastern (MID) AF: 0.00174 AC: 5 AN: 2881

European-Non Finnish (NFE) AF: 0.000336 AC: 90 AN: 268196

Other (OTH) AF: 0.00847 AC: 209 AN: 24670

GnomAD4 genome AF: 0.0259 AC: 2909 AN: 112147 Hom.: 108 Cov.: 23 AF XY: 0.0228 AC XY: 782 AN XY: 34313

African (AFR) AF: 0.0896 AC: 2759 AN: 30789

American (AMR) AF: 0.00980 AC: 104 AN: 10608

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.000367 AC: 1 AN: 2728

European-Finnish (FIN) AF: 0.000327 AC: 2 AN: 6109

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53260

Other (OTH) AF: 0.0184 AC: 28 AN: 1524

Alfa AF: 0.0000732 Hom.: 0

Bravo AF: 0.0304

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.0
DANN	Benign	0.49
PhyloP100		1.9
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: rs29285; hg19: chrX-147019486;