chr7-157175008-A-G

Position:

• chr7-157175008-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014671.3(UBE3C):​c.432A>G​(p.Ile144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3C NM_014671.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

UBE3C (HGNC:16803): (ubiquitin protein ligase E3C) Enables ubiquitin protein ligase activity. Involved in protein polyubiquitination. Predicted to be located in nucleus. Predicted to be part of proteasome complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41651002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3C	NM_014671.3	c.432A>G	p.Ile144Met	missense_variant	5/23	ENST00000348165.10	NP_055486.2
UBE3C	XM_047421072.1	c.369A>G	p.Ile123Met	missense_variant	5/23		XP_047277028.1
UBE3C	XM_005249564.5	c.357A>G	p.Ile119Met	missense_variant	4/22		XP_005249621.1
UBE3C	XM_047421073.1	c.432A>G	p.Ile144Met	missense_variant	5/16		XP_047277029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3C	ENST00000348165.10	c.432A>G	p.Ile144Met	missense_variant	5/23	1	NM_014671.3	ENSP00000309198	P1
UBE3C	ENST00000389103.4	c.303A>G	p.Ile101Met	missense_variant	3/9	5		ENSP00000373755

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.432A>G (p.I144M) alteration is located in exon 5 (coding exon 5) of the UBE3C gene. This alteration results from a A to G substitution at nucleotide position 432, causing the isoleucine (I) at amino acid position 144 to be replaced by a methionine (M). 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	Benign	0.082
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.19
Sift	Benign	0.092	T;.;D
Sift4G	Benign	0.11	T;D;D
Polyphen		0.50	P;P;P
Vest4		0.68
MutPred		0.45		Gain of catalytic residue at I144 (P = 0.0127);.;.;
MVP		0.13
MPC		0.21
ClinPred		0.37	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1210140034; hg19: chr7-156967702;