rs782265090

Positions:

chrX-147930136-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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 (★).

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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 id is 211029.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000448 (5/111610) while in subpopulation SAS AF= 0.00187 (5/2672). AF 95% confidence interval is 0.000737. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMR1	NM_002024.6 linkuse as main transcript	c.522T>A	p.Asn174Lys	missense_variant	7/17	ENST00000370475.9	NP_002015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMR1	ENST00000370475.9 linkuse as main transcript	c.522T>A	p.Asn174Lys	missense_variant	7/17	1	NM_002024.6	ENSP00000359506	P3	Q06787-1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111610

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33804

show subpopulations

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

GnomAD3 exomes

AF:

0.000235

AC:

AN:

183260

Hom.:

AF XY:

0.000487

AC XY:

AN XY:

67768

show subpopulations

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 SAS exome

AF:

0.00220

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.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

352711

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00202

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000601

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111610

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33804

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000296

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.090

T;.;.;.;.;T;T;.;T;T;T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;.;D;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.017

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;M;M;M;.;.;.;.;M;.;.;M

MutationTaster

Benign

0.98

D;D;D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

.;D;D;.;D;.;D;D;D;.;.;D

REVEL

Benign

0.059

Sift

Benign

0.24

.;T;T;.;T;.;T;T;T;.;.;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.53, 0.088, 0.13, 0.040

.;.;.;P;.;B;B;B;B;.;.;.

Vest4

0.46

MutPred

0.35

Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);Gain of ubiquitination at N174 (P = 0.0219);.;Gain of ubiquitination at N174 (P = 0.0219);

MVP

0.73

MPC

1.1

ClinPred

0.091

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over