Genetic Variant UBL4A:p.Glu83Lys (chrX-154485887-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014235.5(UBL4A):c.247G>A(p.Glu83Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,541 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 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. E83Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

UBL4A
NM_014235.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.01

Publications

0 publications found

Variant links:

Genes affected

UBL4A (HGNC:12505): (ubiquitin like 4A) Enables chaperone binding activity. Involved in tail-anchored membrane protein insertion into ER membrane. Located in cytosol; membrane; and nucleoplasm. Part of BAT3 complex. [provided by Alliance of Genome Resources, Apr 2022]

UBL4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09166917).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBL4A	NM_014235.5	MANE Select	c.247G>A	p.Glu83Lys	missense	Exon 3 of 4	NP_055050.1	P11441

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBL4A	ENST00000369660.9	TSL:1 MANE Select	c.247G>A	p.Glu83Lys	missense	Exon 3 of 4	ENSP00000358674.4	P11441
UBL4A	ENST00000369653.8	TSL:3	c.247G>A	p.Glu83Lys	missense	Exon 3 of 5	ENSP00000358667.4	Q5HY81
UBL4A	ENST00000417913.1	TSL:5	n.*39G>A		non_coding_transcript_exon	Exon 3 of 4	ENSP00000397223.1	F8WB70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

180564

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000145

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097541

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363013

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

35155

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841978

Other (OTH)

AF:

0.00

AC:

AN:

46072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.11

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.031

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0056

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-3.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.19

REVEL

Benign

0.0060

Sift

Benign

0.19

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.13

MutPred

0.43

Gain of ubiquitination at E83 (P = 0.0085)

MVP

0.76

MPC

0.55

ClinPred

0.034

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.51

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over