4-88669900-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_014606.3(HERC3):c.1674G>T(p.Lys558Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HERC3
NM_014606.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

Variant links:

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]

HERC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2732876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC3	NM_014606.3 linkuse as main transcript	c.1674G>T	p.Lys558Asn	missense_variant	15/26	ENST00000402738.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC3	ENST00000402738.6 linkuse as main transcript	c.1674G>T	p.Lys558Asn	missense_variant	15/26	1	NM_014606.3	P1	Q15034-1
HERC3	ENST00000264345.7 linkuse as main transcript	c.1674G>T	p.Lys558Asn	missense_variant	13/24	1		P1	Q15034-1
HERC3	ENST00000470815.1 linkuse as main transcript	n.377G>T		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726964

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.1674G>T (p.K558N) alteration is located in exon 15 (coding exon 13) of the HERC3 gene. This alteration results from a G to T substitution at nucleotide position 1674, causing the lysine (K) at amino acid position 558 to be replaced by an asparagine (N). 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

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.010

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.093

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.87

P;P

Vest4

0.29

MutPred

0.52

Loss of ubiquitination at K558 (P = 0.0412);Loss of ubiquitination at K558 (P = 0.0412);

MVP

0.42

MPC

0.67

ClinPred

0.88

GERP RS

4.2

Varity_R

0.32

gMVP

0.48

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

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