X-147950018-C-T

Variant names:

• chrX-147950018-C-T
• rs25704
• ENST00000620828.4:n.3729C>T

Variant summary

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

The ENST00000620828.4(FMR1):​n.3729C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 312,594 control chromosomes in the GnomAD database, including 13,110 homozygotes. There are 33,696 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 0.38 (6973 hom., 11510 hem., cov: 22)
  • Exomes 𝑓: 0.29 (6137 hom. 22186 hem.)
• Consequence: FMR1 ENST00000620828.4 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149
• Publications: 14 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.*1174C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.*1174C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.375 AC: 40949 AN: 109143 Hom.: 6973 Cov.: 22

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.326 AC: 28129 AN: 86159 AF XY: 0.308

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.719

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.285 AC: 58029 AN: 203408 Hom.: 6137 Cov.: 0 AF XY: 0.278 AC XY: 22186 AN XY: 79698

African (AFR) AF: 0.636 AC: 3637 AN: 5716

American (AMR) AF: 0.356 AC: 6510 AN: 18282

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 1273 AN: 7429

East Asian (EAS) AF: 0.708 AC: 4703 AN: 6640

South Asian (SAS) AF: 0.272 AC: 8734 AN: 32056

European-Finnish (FIN) AF: 0.251 AC: 2369 AN: 9425

Middle Eastern (MID) AF: 0.342 AC: 254 AN: 742

European-Non Finnish (NFE) AF: 0.243 AC: 27512 AN: 113332

Other (OTH) AF: 0.310 AC: 3037 AN: 9786

GnomAD4 genome AF: 0.375 AC: 40976 AN: 109186 Hom.: 6973 Cov.: 22 AF XY: 0.364 AC XY: 11510 AN XY: 31658

African (AFR) AF: 0.629 AC: 18909 AN: 30043

American (AMR) AF: 0.364 AC: 3734 AN: 10250

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 438 AN: 2624

East Asian (EAS) AF: 0.705 AC: 2422 AN: 3435

South Asian (SAS) AF: 0.275 AC: 714 AN: 2592

European-Finnish (FIN) AF: 0.235 AC: 1292 AN: 5499

Middle Eastern (MID) AF: 0.308 AC: 65 AN: 211

European-Non Finnish (NFE) AF: 0.240 AC: 12572 AN: 52382

Other (OTH) AF: 0.395 AC: 586 AN: 1483

Alfa AF: 0.284 Hom.: 16739

Bravo AF: 0.407

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.23
DANN	Benign	0.42
PhyloP100		0.15
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: rs25704; hg19: chrX-147031538;