Genetic Variant NM_003334.4:c.1048C>A (chrX-47202496-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003334.4(UBA1):c.1048C>A(p.Arg350Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,260 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

0 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 Gene-Disease associations (from GenCC):

infantile-onset X-linked spinal muscular atrophy
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
inflammatory disease
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

UBA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11128026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4 link	c.1048C>A	p.Arg350Ser	missense_variant	Exon 10 of 26	ENST00000335972.11	NP_003325.2	P22314-1A0A024R1A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBA1	ENST00000335972.11 link	c.1048C>A	p.Arg350Ser	missense_variant	Exon 10 of 26	1	NM_003334.4	ENSP00000338413.6	P22314-1
UBA1	ENST00000377351.8 link	c.1048C>A	p.Arg350Ser	missense_variant	Exon 10 of 26	1		ENSP00000366568.4	P22314-1
UBA1	ENST00000490869.1 link	n.-197C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.20e-7

AC:

AN:

1087260

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

355206

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26133

American (AMR)

AF:

0.00

AC:

AN:

33736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19216

East Asian (EAS)

AF:

0.0000339

AC:

AN:

29471

South Asian (SAS)

AF:

0.00

AC:

AN:

52674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836772

Other (OTH)

AF:

0.00

AC:

AN:

45617

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;.

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

PhyloP100

1.6

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.038

Sift

Benign

0.40

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.042

B;B

Vest4

0.25

MutPred

0.28

Gain of phosphorylation at R350 (P = 0.0247);Gain of phosphorylation at R350 (P = 0.0247);

MVP

0.24

MPC

0.52

ClinPred

0.58

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.74

gMVP

0.64

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over