rs1294727193

Variant names:

• chr7-157178758-C-G
• rs1294727193
• NM_014671.3:c.527C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-157178758-C-G
• chr7-157178758-C-T

Variant summary

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

The NM_014671.3(UBE3C):​c.527C>G​(p.Ser176Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S176L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UBE3C NM_014671.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with absent speech and movement and behavioral abnormalities

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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, 0.841

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014671.3. 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
	UBE3C	NM_014671.3	MANE Select	c.527C>G	p.Ser176Trp	missense	Exon 6 of 23	NP_055486.2	Q15386-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3C	ENST00000348165.10	TSL:1 MANE Select	c.527C>G	p.Ser176Trp	missense	Exon 6 of 23	ENSP00000309198.8	Q15386-1
	UBE3C	ENST00000945962.1		c.527C>G	p.Ser176Trp	missense	Exon 6 of 24	ENSP00000616021.1
	UBE3C	ENST00000945960.1		c.602C>G	p.Ser201Trp	missense	Exon 7 of 24	ENSP00000616019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.78
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.55		Loss of disorder (P = 0.0659)
MVP		0.32
MPC		0.89
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.43
gMVP		0.78
Mutation Taster		=56/44	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: rs1294727193; hg19: chr7-156971452;