Genetic Variant UBA6:p.Asp1035Gly (chr4-67619052-T-C) – 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_018227.6(UBA6):c.3104A>G(p.Asp1035Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00056 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

UBA6
NM_018227.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.00

Publications

2 publications found

Variant links:

Genes affected

UBA6 (HGNC:25581): (ubiquitin like modifier activating enzyme 6) Modification of proteins with ubiquitin (UBB; MIM 191339) or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin-activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3). UBE1L2 is an E1 enzyme that initiates the activation and conjugation of ubiquitin-like proteins (Jin et al., 2007 [PubMed 17597759]).[supplied by OMIM, Mar 2008]

UBA6 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

UBA6 links:

Genome browser will be placed here

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=0.08570522).

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA6	NM_018227.6 link	c.3104A>G	p.Asp1035Gly	missense_variant	Exon 33 of 33	ENST00000322244.10	NP_060697.4	A0AVT1-1A1LT96
UBA6	XM_017008359.3 link	c.*6A>G		3_prime_UTR_variant	Exon 33 of 33		XP_016863848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBA6	ENST00000322244.10 link	c.3104A>G	p.Asp1035Gly	missense_variant	Exon 33 of 33	1	NM_018227.6	ENSP00000313454.4	A0AVT1-1
UBA6	ENST00000514261.1 link	n.*159A>G		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000425091.1	H0Y9U5
UBA6	ENST00000514261.1 link	n.*159A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000425091.1	H0Y9U5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000176

AC:

AN:

250402

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000585

AC:

855

AN:

1461326

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

426

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33464

American (AMR)

AF:

0.000291

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000722

AC:

802

AN:

1111556

Other (OTH)

AF:

0.000613

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000315

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41458

American (AMR)

AF:

0.000458

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000487

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3104A>G (p.D1035G) alteration is located in exon 33 (coding exon 33) of the UBA6 gene. This alteration results from a A to G substitution at nucleotide position 3104, causing the aspartic acid (D) at amino acid position 1035 to be replaced by a glycine (G). 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

Benign

0.16

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.19

Eigen_PC

Benign

0.042

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.011

MetaRNN

Benign

0.086

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

PhyloP100

7.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.3

REVEL

Benign

0.14

Sift

Benign

0.58

Sift4G

Benign

0.33

Polyphen

0.0020

Vest4

0.27

MVP

0.12

MPC

0.20

ClinPred

0.090

GERP RS

4.9

Varity_R

0.21

gMVP

0.45

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

4-67619052-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over