Genetic Variant UBE3C:p.Tyr105His (chr7-157170421-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014671.3(UBE3C):c.313T>C(p.Tyr105His) variant causes a missense change. The variant allele was found at a frequency of 0.0000227 in 1,409,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

UBE3C
NM_014671.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

Variant links:

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]

UBE3C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3C	NM_014671.3 link	c.313T>C	p.Tyr105His	missense_variant	Exon 4 of 23	ENST00000348165.10	NP_055486.2	Q15386-1
UBE3C	XM_047421072.1 link	c.250T>C	p.Tyr84His	missense_variant	Exon 4 of 23		XP_047277028.1
UBE3C	XM_005249564.5 link	c.238T>C	p.Tyr80His	missense_variant	Exon 3 of 22		XP_005249621.1
UBE3C	XM_047421073.1 link	c.313T>C	p.Tyr105His	missense_variant	Exon 4 of 16		XP_047277029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBE3C	ENST00000348165.10 link	c.313T>C	p.Tyr105His	missense_variant	Exon 4 of 23	1	NM_014671.3	ENSP00000309198.8	Q15386-1
UBE3C	ENST00000389103.4 link	c.184T>C	p.Tyr62His	missense_variant	Exon 2 of 9	5		ENSP00000373755.4	Q15386-3
UBE3C	ENST00000430750.1 link	n.*248T>C		non_coding_transcript_exon_variant	Exon 5 of 5	4		ENSP00000397432.1	H7C0Y1
UBE3C	ENST00000430750.1 link	n.*248T>C		3_prime_UTR_variant	Exon 5 of 5	4		ENSP00000397432.1	H7C0Y1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000143

AC:

AN:

209644

Hom.:

AF XY:

0.0000175

AC XY:

AN XY:

114216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000297

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1409414

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

700490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000293

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313T>C (p.Y105H) alteration is located in exon 4 (coding exon 4) of the UBE3C gene. This alteration results from a T to C substitution at nucleotide position 313, causing the tyrosine (Y) at amino acid position 105 to be replaced by a histidine (H). 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.5

D;.;D

REVEL

Uncertain

0.37

Sift

Benign

0.054

T;.;D

Sift4G

Benign

0.062

T;D;D

Polyphen

1.0

D;D;D

Vest4

0.88

MutPred

0.72

Loss of sheet (P = 0.0228);.;.;

MVP

0.25

MPC

0.71

ClinPred

0.87

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over