Genetic Variant UBL4A:p.Thr4Lys (chrX-154486574-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014235.5(UBL4A):c.11C>A(p.Thr4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 970,040 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 0.0000012 ( 0 hom. 0 hem. )

Consequence

UBL4A
NM_014235.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.223

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBL4A	NM_014235.5 link	c.11C>A	p.Thr4Lys	missense_variant	Exon 1 of 4	ENST00000369660.9	NP_055050.1	P11441

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBL4A	ENST00000369660.9 link	c.11C>A	p.Thr4Lys	missense_variant	Exon 1 of 4	1	NM_014235.5	ENSP00000358674.4		P11441

Frequencies

GnomAD3 genomes

AF:

0.00000932

AC:

AN:

107290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31014

show subpopulations

Gnomad AFR

AF:

0.0000335

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000116

AC:

AN:

862750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

264482

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000139

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000932

AC:

AN:

107290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31014

show subpopulations

Gnomad4 AFR

AF:

0.0000335

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>A (p.T4K) alteration is located in exon 1 (coding exon 1) of the UBL4A gene. This alteration results from a C to A substitution at nucleotide position 11, causing the threonine (T) at amino acid position 4 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

T;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

T;T;T

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Benign

0.25

Sift

Benign

0.071

T;T;.

Sift4G

Benign

0.12

T;T;D

Polyphen

1.0

D;.;.

Vest4

0.38

MutPred

0.42

Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);

MVP

0.90

MPC

1.0

ClinPred

0.95

GERP RS

4.0

Varity_R

0.64

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -1

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