rs28900

Variant names:

• chrX-147912583-C-A
• rs28900
• NM_002024.6:c.51+353C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-147912583-C-A
• chrX-147912583-C-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.51+353C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0974 in 303,910 control chromosomes in the GnomAD database, including 2,647 homozygotes. There are 9,519 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 0.078 (650 hom., 2806 hem., cov: 24)
  • Exomes 𝑓: 0.11 (1997 hom. 6713 hem.)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314
• Publications: 4 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.51+353C>A		intron_variant	Intron 1 of 16	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9	c.51+353C>A		intron_variant	Intron 1 of 16	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 8761 AN: 112520 Hom.: 652 Cov.: 24

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.0538

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.0504

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.109 AC: 20821 AN: 191332 Hom.: 1997 AF XY: 0.108 AC XY: 6713 AN XY: 61962

African (AFR) AF: 0.0214 AC: 130 AN: 6084

American (AMR) AF: 0.235 AC: 1558 AN: 6639

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 323 AN: 6828

East Asian (EAS) AF: 0.501 AC: 8977 AN: 17901

South Asian (SAS) AF: 0.125 AC: 425 AN: 3407

European-Finnish (FIN) AF: 0.0579 AC: 926 AN: 15986

Middle Eastern (MID) AF: 0.0941 AC: 87 AN: 925

European-Non Finnish (NFE) AF: 0.0582 AC: 7025 AN: 120609

Other (OTH) AF: 0.106 AC: 1370 AN: 12953

GnomAD4 genome AF: 0.0779 AC: 8769 AN: 112578 Hom.: 650 Cov.: 24 AF XY: 0.0807 AC XY: 2806 AN XY: 34772

African (AFR) AF: 0.0204 AC: 635 AN: 31098

American (AMR) AF: 0.209 AC: 2249 AN: 10781

Ashkenazi Jewish (ASJ) AF: 0.0538 AC: 143 AN: 2657

East Asian (EAS) AF: 0.569 AC: 1963 AN: 3451

South Asian (SAS) AF: 0.105 AC: 290 AN: 2750

European-Finnish (FIN) AF: 0.0505 AC: 316 AN: 6259

Middle Eastern (MID) AF: 0.0507 AC: 11 AN: 217

European-Non Finnish (NFE) AF: 0.0538 AC: 2858 AN: 53144

Other (OTH) AF: 0.116 AC: 179 AN: 1540

Alfa AF: 0.0687 Hom.: 4444

Bravo AF: 0.0967

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.8
DANN	Benign	0.82
PhyloP100		0.31
PromoterAI		-0.011	Neutral
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: rs28900; hg19: chrX-146994101;