rs29281

Positions:

• chrX-147929961-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002024.6(FMR1):​c.433G>T​(p.Ala145Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 1,191,575 control chromosomes in the GnomAD database, including 192 homozygotes. There are 1,528 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (103 hom., 727 hem., cov: 22)
  • Exomes 𝑓: 0.0029 (89 hom. 801 hem.)
• Consequence: FMR1 NM_002024.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017594695).
• BP6: Variant X-147929961-G-T is Benign according to our data. Variant chrX-147929961-G-T is described in ClinVar as [Benign]. Clinvar id is 129104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMR1	NM_002024.6	c.433G>T	p.Ala145Ser	missense_variant	6/17	ENST00000370475.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMR1	ENST00000370475.9	c.433G>T	p.Ala145Ser	missense_variant	6/17	1	NM_002024.6	P3

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 2820 AN: 110893 Hom.: 103 Cov.: 22 AF XY: 0.0217 AC XY: 721 AN XY: 33203

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00931

Gnomad ASJ AF: 0.000758

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.000506

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.0188

GnomAD3 exomes AF: 0.00772 AC: 1396 AN: 180837 Hom.: 48 AF XY: 0.00445 AC XY: 293 AN XY: 65783

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000268

Gnomad FIN exome AF: 0.000503

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00289 AC: 3122 AN: 1080631 Hom.: 89 Cov.: 28 AF XY: 0.00230 AC XY: 801 AN XY: 348921

Gnomad4 AFR exome AF: 0.0893

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.000392

Gnomad4 FIN exome AF: 0.000741

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.0255 AC: 2826 AN: 110944 Hom.: 103 Cov.: 22 AF XY: 0.0219 AC XY: 727 AN XY: 33264

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.00930

Gnomad4 ASJ AF: 0.000758

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.000506

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.0186

Alfa AF: 0.00526 Hom.: 131

Bravo AF: 0.0303

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0920 AC: 353

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.00850 AC: 1032

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fragile X syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Fragile X syndrome;C1839780:Fragile X-associated tremor/ataxia syndrome;C4552079:Premature ovarian failure 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.15
DEOGEN2	Benign	0.0050	T;.;.;.;.;T;T;.;T;T;T;.
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T;T;T;T;T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;B;B;B;B;.;.;.
Vest4		0.11
MVP		0.62
MPC		0.81
ClinPred		0.0020	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs29281; hg19: chrX-147011480; COSMIC: COSV54425690; COSMIC: COSV54425690;