NM_018227.6:c.3043C>T

Variant names:

• chr4-67619113-G-A
• rs377289306
• NM_018227.6:c.3043C>T

Variant summary

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

The NM_018227.6(UBA6):​c.3043C>T​(p.Pro1015Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,604,994 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. P1015H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBA6 NM_018227.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA6	NM_018227.6	c.3043C>T	p.Pro1015Ser	missense_variant	Exon 33 of 33	ENST00000322244.10	NP_060697.4
UBA6	XM_017008359.3	c.3024-49C>T		intron_variant	Intron 32 of 32		XP_016863848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA6	ENST00000322244.10	c.3043C>T	p.Pro1015Ser	missense_variant	Exon 33 of 33	1	NM_018227.6	ENSP00000313454.4
UBA6	ENST00000514261.1	n.*98C>T		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000425091.1
UBA6	ENST00000514261.1	n.*98C>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000425091.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00000813 AC: 2 AN: 245986 AF XY: 0.0000150

Gnomad AFR exome AF: 0.000124

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: 6.88e-7 AC: 1 AN: 1452892 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723082

African (AFR) AF: 0.0000301 AC: 1 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 44178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105316

Other (OTH) AF: 0.00 AC: 0 AN: 60072

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

African (AFR) AF: 0.000121 AC: 5 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3043C>T (p.P1015S) alteration is located in exon 33 (coding exon 33) of the UBA6 gene. This alteration results from a C to T substitution at nucleotide position 3043, causing the proline (P) at amino acid position 1015 to be replaced by a serine (S). 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	0.60
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Benign	0.67
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Benign	0.68	T
Sift4G	Benign	0.70	T
Polyphen		0.98	D
Vest4		0.55
MVP		0.10
MPC		0.18
ClinPred		0.55	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.35
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs377289306; hg19: chr4-68484831;