rs146180431

Positions:

chrX-47202413-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4BP6_Very_StrongBS2

The NM_003334.4(UBA1):c.965A>G(p.Lys322Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,208,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 121 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 0.00015 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.00031 ( 0 hom. 120 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.38

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 Benign. Variant got -12 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=0.29098848).

BP6

Variant X-47202413-A-G is Benign according to our data. Variant chrX-47202413-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 465037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47202413-A-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome4 at 120 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA1	NM_003334.4 linkuse as main transcript	c.965A>G	p.Lys322Arg	missense_variant	10/26	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.965A>G	p.Lys322Arg	missense_variant	10/26	1	NM_003334.4	ENSP00000338413.6		P22314-1
UBA1	ENST00000377351.8 linkuse as main transcript	c.965A>G	p.Lys322Arg	missense_variant	10/26	1		ENSP00000366568.4		P22314-1

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

112164

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34330

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

178388

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

63224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000738

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000467

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000305

AC:

335

AN:

1096693

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

120

AN XY:

362119

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000570

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000152

AC:

AN:

112164

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34330

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2020

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

Dec 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.99

D;D

Vest4

0.36

MVP

0.69

MPC

1.1

ClinPred

0.34

GERP RS

4.8

Varity_R

0.84

gMVP

0.70

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