rs4949

Variant names:

• chrX-147917663-A-G
• rs4949
• NM_002024.6:c.52-4270A>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.52-4270A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 110,747 control chromosomes in the GnomAD database, including 11,490 homozygotes. There are 16,398 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 0.51 (11490 hom., 16398 hem., cov: 23)
• Consequence: FMR1 NM_002024.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMR1	NM_002024.6	c.52-4270A>G		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.52-4270A>G		intron_variant	Intron 1 of 16	1	NM_002024.6	ENSP00000359506.5

Frequencies

GnomAD3 genomes AF: 0.511 AC: 56555 AN: 110698 Hom.: 11493 Cov.: 23

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.448

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.519

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.511 AC: 56593 AN: 110747 Hom.: 11490 Cov.: 23 AF XY: 0.497 AC XY: 16398 AN XY: 32985

African (AFR) AF: 0.754 AC: 22911 AN: 30375

American (AMR) AF: 0.453 AC: 4779 AN: 10545

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 822 AN: 2637

East Asian (EAS) AF: 0.716 AC: 2510 AN: 3506

South Asian (SAS) AF: 0.443 AC: 1176 AN: 2656

European-Finnish (FIN) AF: 0.390 AC: 2283 AN: 5860

Middle Eastern (MID) AF: 0.443 AC: 93 AN: 210

European-Non Finnish (NFE) AF: 0.396 AC: 20881 AN: 52782

Other (OTH) AF: 0.520 AC: 783 AN: 1505

Alfa AF: 0.459 Hom.: 3276

Bravo AF: 0.536

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.82
PhyloP100		-0.10
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: rs4949; hg19: chrX-146999181;