rs782265090

Variant names:

• chrX-147930136-T-A
• rs782265090
• NM_002024.6:c.522T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002024.6(FMR1):​c.522T>A​(p.Asn174Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,198,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N174S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 79 hem.)
• Consequence: FMR1 NM_002024.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08
• 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: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• fragile X-associated tremor/ataxia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• symptomatic form of fragile X syndrome in female carrier

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016963959).
• BP6: Variant X-147930136-T-A is Benign according to our data. Variant chrX-147930136-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 211029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	NM_002024.6	MANE Select	c.522T>A	p.Asn174Lys	missense	Exon 7 of 17	NP_002015.1	Q06787-1
	FMR1	NM_001185076.2		c.522T>A	p.Asn174Lys	missense	Exon 7 of 16	NP_001172005.1	Q06787-9
	FMR1	NM_001185082.2		c.522T>A	p.Asn174Lys	missense	Exon 7 of 16	NP_001172011.1	Q06787-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMR1	ENST00000370475.9	TSL:1 MANE Select	c.522T>A	p.Asn174Lys	missense	Exon 7 of 17	ENSP00000359506.5	Q06787-1
	FMR1	ENST00000218200.12	TSL:1	c.522T>A	p.Asn174Lys	missense	Exon 7 of 16	ENSP00000218200.8	Q06787-9
	FMR1	ENST00000439526.6	TSL:1	c.522T>A	p.Asn174Lys	missense	Exon 7 of 16	ENSP00000395923.2	G3V0J0

Frequencies

GnomAD3 genomes AF: 0.0000448 AC: 5 AN: 111610 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 43 AN: 183260 AF XY: 0.000487

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: 0.000106 AC: 115 AN: 1086605 Hom.: 0 Cov.: 29 AF XY: 0.000224 AC XY: 79 AN XY: 352711

African (AFR) AF: 0.00 AC: 0 AN: 26169

American (AMR) AF: 0.00 AC: 0 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19294

East Asian (EAS) AF: 0.00 AC: 0 AN: 30165

South Asian (SAS) AF: 0.00202 AC: 109 AN: 53887

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000601 AC: 5 AN: 831552

Other (OTH) AF: 0.0000219 AC: 1 AN: 45723

GnomAD4 genome AF: 0.0000448 AC: 5 AN: 111610 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33804

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30654

American (AMR) AF: 0.00 AC: 0 AN: 10533

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00187 AC: 5 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53139

Other (OTH) AF: 0.00 AC: 0 AN: 1498

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000296 AC: 36

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.73
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.059
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.53	P
Vest4		0.46
MutPred		0.35		Gain of ubiquitination at N174 (P = 0.0219)
MVP		0.73
MPC		1.1
ClinPred		0.091	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.74
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782265090; hg19: chrX-147011655;