rs797045582

Variant names:

• chrX-147928762-C-T
• rs797045582
• NM_002024.6:c.374C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002024.6(FMR1):​c.374C>T​(p.Thr125Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,097,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: FMR1 NM_002024.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4223452).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.374C>T	p.Thr125Ile	missense	Exon 5 of 17	NP_002015.1
	FMR1	NM_001185076.2		c.374C>T	p.Thr125Ile	missense	Exon 5 of 16	NP_001172005.1
	FMR1	NM_001185082.2		c.374C>T	p.Thr125Ile	missense	Exon 5 of 16	NP_001172011.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.374C>T	p.Thr125Ile	missense	Exon 5 of 17	ENSP00000359506.5
	FMR1	ENST00000218200.12	TSL:1	c.374C>T	p.Thr125Ile	missense	Exon 5 of 16	ENSP00000218200.8
	FMR1	ENST00000439526.6	TSL:1	c.374C>T	p.Thr125Ile	missense	Exon 5 of 16	ENSP00000395923.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183152 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097158 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 362662

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00 AC: 0 AN: 54096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841250

Other (OTH) AF: 0.00 AC: 0 AN: 46063

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.0031	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.28		Loss of disorder (P = 0.0495)
MVP		0.86
MPC		2.0
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.78
Mutation Taster		=34/66	disease causing

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: rs797045582; hg19: chrX-147010280;