4-88670013-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014606.3(HERC3):c.1787A>G(p.Lys596Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HERC3 NM_014606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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 Uncertain_significance. Variant got 2 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=0.41404033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC3	NM_014606.3	c.1787A>G	p.Lys596Arg	missense_variant	15/26	ENST00000402738.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC3	ENST00000402738.6	c.1787A>G	p.Lys596Arg	missense_variant	15/26	1	NM_014606.3	P1
HERC3	ENST00000264345.7	c.1787A>G	p.Lys596Arg	missense_variant	13/24	1		P1
HERC3	ENST00000470815.1	n.490A>G		non_coding_transcript_exon_variant	3/4	4

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

Feb 23, 2023

The c.1787A>G (p.K596R) alteration is located in exon 15 (coding exon 13) of the HERC3 gene. This alteration results from a A to G substitution at nucleotide position 1787, causing the lysine (K) at amino acid position 596 to be replaced by an arginine (R). 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	0.23
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.33	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.89	P;P
Vest4		0.58
MutPred		0.42		Loss of ubiquitination at K596 (P = 0.0496);Loss of ubiquitination at K596 (P = 0.0496);
MVP		0.33
MPC		1.4
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-89591164;