X-47200987-C-T

Position:

chrX-47200987-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_003334.4(UBA1):c.574C>T(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,197,425 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000030 ( 0 hom. 14 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.237

Variant links:

Genes affected

UBA1 (HGNC:12469): (ubiquitin like modifier activating enzyme 1) The protein encoded by this gene catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation. This gene complements an X-linked mouse temperature-sensitive defect in DNA synthesis, and thus may function in DNA repair. It is part of a gene cluster on chromosome Xp11.23. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Jul 2008]

UBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBA1. . Gene score misZ 3.4752 (greater than the threshold 3.09). GenCC has associacion of gene with infantile-onset X-linked spinal muscular atrophy, inflammatory disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.35817844).

BP6

Variant X-47200987-C-T is Benign according to our data. Variant chrX-47200987-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533611.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA1	NM_003334.4 linkuse as main transcript	c.574C>T	p.Arg192Trp	missense_variant	6/26	ENST00000335972.11	NP_003325.2	P22314-1A0A024R1A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11 linkuse as main transcript	c.574C>T	p.Arg192Trp	missense_variant	6/26	1	NM_003334.4	ENSP00000338413.6		P22314-1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112117

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34289

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000697

AC:

AN:

157811

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

50079

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000791

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000566

Gnomad SAS exome

AF:

0.0000615

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1085308

Hom.:

Cov.:

AF XY:

0.0000396

AC XY:

AN XY:

353460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000591

Gnomad4 ASJ exome

AF:

0.0000523

Gnomad4 EAS exome

AF:

0.000270

Gnomad4 SAS exome

AF:

0.0000769

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000658

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112117

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34289

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000562

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000666

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

This alteration is classified as likely 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. -

Infantile-onset X-linked spinal muscular atrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;.;T;T

FATHMM_MKL

Benign

0.22

LIST_S2

Pathogenic

0.97

D;D;D;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

M;.;.;M

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.2

D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.014

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.81

P;.;.;P

Vest4

0.57

MutPred

0.71

Loss of methylation at R192 (P = 0.0479);Loss of methylation at R192 (P = 0.0479);.;Loss of methylation at R192 (P = 0.0479);

MVP

0.55

MPC

1.3

ClinPred

0.35

GERP RS

-0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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