Genetic Variant NM_018227.6:c.60G>C (chr4-67701060-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018227.6(UBA6):c.60G>C(p.Trp20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

UBA6
NM_018227.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

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 links:

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

UBA6-DT links:

Genome browser will be placed here

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
UBA6	NM_018227.6 link	c.60G>C	p.Trp20Cys	missense_variant	Exon 1 of 33	ENST00000322244.10	NP_060697.4	A0AVT1-1A1LT96
UBA6	XM_017008359.3 link	c.60G>C	p.Trp20Cys	missense_variant	Exon 1 of 33		XP_016863848.1
UBA6	XM_047415893.1 link	c.60G>C	p.Trp20Cys	missense_variant	Exon 1 of 28		XP_047271849.1
UBA6-DT	NR_015439.1 link	n.-218C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA6	ENST00000322244.10 link	c.60G>C	p.Trp20Cys	missense_variant	Exon 1 of 33	1	NM_018227.6	ENSP00000313454.4		A0AVT1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249224

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727066

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.60G>C (p.W20C) alteration is located in exon 1 (coding exon 1) of the UBA6 gene. This alteration results from a G to C substitution at nucleotide position 60, causing the tryptophan (W) at amino acid position 20 to be replaced by a cysteine (C). 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

0.20

BayesDel_addAF

Benign

-0.0056

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.17

Sift

Benign

0.18

T;T

Sift4G

Benign

0.18

T;T

Polyphen

1.0

D;D

Vest4

0.61

MutPred

0.25

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.35

MPC

0.38

ClinPred

0.64

GERP RS

3.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.13

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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