19-58558348-T-C

Variant names:

• chr19-58558348-T-C
• rs371025308
• NM_003969.4:c.34A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003969.4(UBE2M):​c.34A>G​(p.Lys12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000568 in 1,585,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: UBE2M NM_003969.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 2 publications found

Genes affected

UBE2M (HGNC:12491): (ubiquitin conjugating enzyme E2 M) 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 E2 ubiquitin-conjugating enzyme family. The encoded protein is linked with a ubiquitin-like protein, NEDD8, which can be conjugated to cellular proteins, such as Cdc53/culin. [provided by RefSeq, Jul 2008]

MZF1-AS1 (HGNC:51271): (MZF1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20654488).
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003969.4. 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
	UBE2M	NM_003969.4	MANE Select	c.34A>G	p.Lys12Glu	missense	Exon 1 of 6	NP_003960.1	A0A024R4T4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE2M	ENST00000253023.8	TSL:1 MANE Select	c.34A>G	p.Lys12Glu	missense	Exon 1 of 6	ENSP00000253023.2	P61081-1
	UBE2M	ENST00000940562.1		c.34A>G	p.Lys12Glu	missense	Exon 1 of 6	ENSP00000610621.1
	UBE2M	ENST00000595957.5	TSL:2	c.-258A>G		5_prime_UTR	Exon 2 of 7	ENSP00000468940.1	M0QX69

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000501 AC: 11 AN: 219754 AF XY: 0.0000413

Gnomad AFR exome AF: 0.0000731

Gnomad AMR exome AF: 0.0000644

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000815

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000565 AC: 81 AN: 1434438 Hom.: 0 Cov.: 31 AF XY: 0.0000477 AC XY: 34 AN XY: 713506

African (AFR) AF: 0.0000313 AC: 1 AN: 31998

American (AMR) AF: 0.0000470 AC: 2 AN: 42578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.00 AC: 0 AN: 36202

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84308

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000564 AC: 62 AN: 1099718

Other (OTH) AF: 0.000186 AC: 11 AN: 59188

GnomAD4 genome AF: 0.0000595 AC: 9 AN: 151212 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73830

African (AFR) AF: 0.00 AC: 0 AN: 41296

American (AMR) AF: 0.000131 AC: 2 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67676

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000894 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000579 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.042	D
Sift4G	Benign	0.077	T
Polyphen		0.046	B
Vest4		0.29
MVP		0.59
MPC		1.7
ClinPred		0.057	T
GERP RS		3.7
PromoterAI		0.0059	Neutral
Varity_R		0.54
gMVP		0.81
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs371025308; hg19: chr19-59069715; COSMIC: COSV99285294; COSMIC: COSV99285294;