dbSNP rs1557212992: UBL4A:p.Thr4Lys (chrX-154486574-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.11C>A	p.Thr4Lys	missense	Exon 1 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.11C>A	p.Thr4Lys	missense	Exon 1 of 4	ENSP00000358674.4	P11441
UBL4A	ENST00000369653.8	TSL:3	c.11C>A	p.Thr4Lys	missense	Exon 1 of 5	ENSP00000358667.4	Q5HY81
UBL4A	ENST00000630530.1	TSL:5	c.11C>A	p.Thr4Lys	missense	Exon 1 of 2	ENSP00000486867.1	F8WCT8

Frequencies

GnomAD3 genomes

AF:

0.00000932

AC:

AN:

107290

Hom.:

Cov.:

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

⚠️ 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:

17073

American (AMR)

AF:

0.00

AC:

AN:

12470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12299

East Asian (EAS)

AF:

0.00

AC:

AN:

15982

South Asian (SAS)

AF:

0.00

AC:

AN:

29249

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2096

European-Non Finnish (NFE)

AF:

0.00000139

AC:

AN:

720779

Other (OTH)

AF:

0.00

AC:

AN:

33598

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000932

AC:

AN:

107290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31014

show subpopulations

African (AFR)

AF:

0.0000335

AC:

AN:

29863

American (AMR)

AF:

0.00

AC:

AN:

10348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2594

East Asian (EAS)

AF:

0.00

AC:

AN:

3339

South Asian (SAS)

AF:

0.00

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4866

Middle Eastern (MID)

AF:

0.00

AC:

AN:

229

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51325

Other (OTH)

AF:

0.00

AC:

AN:

1441

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.22

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.25

Sift

Benign

0.071

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.38

MutPred

0.42

Gain of MoRF binding (P = 0.0242)

MVP

0.90

MPC

1.0

ClinPred

0.95

GERP RS

4.0

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.64

gMVP

0.66

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over