4-88653087-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_014606.3(HERC3):c.682A>G(p.Lys228Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HERC3 NM_014606.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.22

Genes affected

HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HERC3
• BP4: Computational evidence support a benign effect (MetaRNN=0.04120004).
• BP6: Variant 4-88653087-A-G is Benign according to our data. Variant chr4-88653087-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2487089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC3	NM_014606.3	c.682A>G	p.Lys228Glu	missense_variant	6/26	ENST00000402738.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC3	ENST00000402738.6	c.682A>G	p.Lys228Glu	missense_variant	6/26	1	NM_014606.3	P1
HERC3	ENST00000264345.7	c.682A>G	p.Lys228Glu	missense_variant	4/24	1		P1
HERC3	ENST00000407637.5	c.682A>G	p.Lys228Glu	missense_variant	6/9	1
HERC3	ENST00000452979.5	c.682A>G	p.Ter228=	incomplete_terminal_codon_variant, coding_sequence_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000597

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Benign	0.73
DEOGEN2	Benign	0.077	T;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.73	N;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.33	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.79	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.12
MutPred		0.43		Loss of ubiquitination at K228 (P = 0.0103);Loss of ubiquitination at K228 (P = 0.0103);Loss of ubiquitination at K228 (P = 0.0103);
MVP		0.14
MPC		0.77
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.046
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs916157675; hg19: chr4-89574238;