dbSNP rs80356546: UBA1:p.Ser547Gly (chrX-47206011-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003334.4(UBA1):c.1639A>G(p.Ser547Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 1.94

Publications

10 publications found

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:

LOC105373194 (HGNC:):

LOC105373194 links:

INE1 (HGNC:6060): (inactivation escape 1) X chromosome inactivation provides dosage compensation for the expression level of X-linked genes from the single X in males and the two in females. This X chromosome gene is intronless and was identified because its transcription escapes X inactivation in females. This gene does not make a protein.[provided by RefSeq, May 2010]

INE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4 link	c.1639A>G	p.Ser547Gly	missense_variant	Exon 15 of 26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
UBA1	ENST00000335972.11 link	c.1639A>G	p.Ser547Gly	missense_variant	Exon 15 of 26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8 link	c.1639A>G	p.Ser547Gly	missense_variant	Exon 15 of 26	1		ENSP00000366568.4
UBA1	ENST00000490869.1 link	n.465-67A>G		intron_variant	Intron 4 of 5	2
INE1	ENST00000456273.1 link	n.*146A>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy

Pathogenic:1Uncertain:1Other:1

Jan 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 07, 2018

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1,PM2,PP5 -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.91

D;.

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.6

L;L

PhyloP100

1.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.0050

B;B

Vest4

0.20

MutPred

0.88

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.91

MPC

0.98

ClinPred

0.30

GERP RS

4.6

Varity_R

0.45

gMVP

0.88

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over