3-49808027-C-G

Variant names:

• chr3-49808027-C-G
• rs118020287
• NM_003335.3:c.2516G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003335.3(UBA7):​c.2516G>C​(p.Arg839Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,614,112 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R839C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: UBA7 NM_003335.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.633
• Publications: 3 publications found

Genes affected

UBA7 (HGNC:12471): (ubiquitin like modifier activating enzyme 7) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme is a retinoid target that triggers promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) degradation and apoptosis in acute promyelocytic leukemia, where it is involved in the conjugation of the ubiquitin-like interferon-stimulated gene 15 protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005392939).
• BP6: Variant 3-49808027-C-G is Benign according to our data. Variant chr3-49808027-C-G is described in ClinVar as Benign. ClinVar VariationId is 3051003.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003335.3. 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
	UBA7	NM_003335.3	MANE Select	c.2516G>C	p.Arg839Pro	missense	Exon 20 of 24	NP_003326.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA7	ENST00000333486.4	TSL:1 MANE Select	c.2516G>C	p.Arg839Pro	missense	Exon 20 of 24	ENSP00000333266.3	P41226
	UBA7	ENST00000905619.1		c.2531G>C	p.Arg844Pro	missense	Exon 20 of 24	ENSP00000575678.1
	UBA7	ENST00000905599.1		c.2516G>C	p.Arg839Pro	missense	Exon 21 of 25	ENSP00000575658.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0150

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: 0.00108 AC: 272 AN: 250752 AF XY: 0.00107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 361 AN: 1461748 Hom.: 2 Cov.: 31 AF XY: 0.000253 AC XY: 184 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00859 AC: 341 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.000298 AC: 18 AN: 60390

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74504

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15308

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

East Asian (EAS) AF: 0.0150 AC: 78 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 127

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	UBA7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.63
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.026	D
Polyphen		0.43	B
Vest4		0.30
MVP		0.25
MPC		0.94
ClinPred		0.31	T
GERP RS		-0.67
Varity_R		0.86
gMVP		0.86
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs118020287; hg19: chr3-49845460;