Genetic Variant NM_018227.6:c.3044C>A (chr4-67619112-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018227.6(UBA6):c.3044C>A(p.Pro1015His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,605,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1015S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

UBA6
NM_018227.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.75

Publications

1 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 -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA6	NM_018227.6 link	c.3044C>A	p.Pro1015His	missense_variant	Exon 33 of 33	ENST00000322244.10	NP_060697.4	A0AVT1-1A1LT96
UBA6	XM_017008359.3 link	c.3024-48C>A		intron_variant	Intron 32 of 32		XP_016863848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBA6	ENST00000322244.10 link	c.3044C>A	p.Pro1015His	missense_variant	Exon 33 of 33	1	NM_018227.6	ENSP00000313454.4	A0AVT1-1
UBA6	ENST00000514261.1 link	n.*99C>A		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000425091.1	H0Y9U5
UBA6	ENST00000514261.1 link	n.*99C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000425091.1	H0Y9U5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

246414

AF XY:

0.00000751

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1453638

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723444

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33246

American (AMR)

AF:

0.00

AC:

AN:

44180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105924

Other (OTH)

AF:

0.00

AC:

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3044C>A (p.P1015H) alteration is located in exon 33 (coding exon 33) of the UBA6 gene. This alteration results from a C to A substitution at nucleotide position 3044, causing the proline (P) at amino acid position 1015 to be replaced by a histidine (H). 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

0.78

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

8.7

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.1

REVEL

Benign

0.23

Sift

Benign

0.39

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.63

MVP

0.093

MPC

0.64

ClinPred

0.68

GERP RS

4.9

Varity_R

0.31

gMVP

0.36

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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NM_018227.6:c.3044C>A

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