chr1-10105570-T-C

Variant names:

• chr1-10105570-T-C
• rs867051886
• NM_001105562.3:c.635T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001105562.3(UBE4B):​c.635T>C​(p.Met212Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. M212L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE4B NM_001105562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

UBE4B (HGNC:12500): (ubiquitination factor E4B) 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 an additional conjugation factor, E4, which is involved in multiubiquitin chain assembly. This gene is also the strongest candidate in the neuroblastoma tumor suppressor genes. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105562.3. 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
	UBE4B	NM_001105562.3	MANE Select	c.635T>C	p.Met212Thr	missense	Exon 6 of 28	NP_001099032.1	O95155-1
	UBE4B	NM_001410744.1		c.635T>C	p.Met212Thr	missense	Exon 6 of 29	NP_001397673.1	O95155-4
	UBE4B	NM_006048.5		c.635T>C	p.Met212Thr	missense	Exon 6 of 27	NP_006039.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4B	ENST00000343090.11	TSL:1 MANE Select	c.635T>C	p.Met212Thr	missense	Exon 6 of 28	ENSP00000343001.6	O95155-1
	UBE4B	ENST00000253251.12	TSL:1	c.635T>C	p.Met212Thr	missense	Exon 6 of 27	ENSP00000253251.8	O95155-2
	UBE4B	ENST00000672724.1		c.635T>C	p.Met212Thr	missense	Exon 6 of 29	ENSP00000500453.1	O95155-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.46
Sift	Benign	0.048	D
Sift4G	Benign	0.55	T
Polyphen		0.81	P
Vest4		0.80
MutPred		0.75		Gain of helix (P = 0.0854)
MVP		0.58
MPC		0.37
ClinPred		0.80	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.65
Mutation Taster		=52/48	polymorphism

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: rs867051886; hg19: chr1-10165628;