Genetic Variant NM_014606.3:c.1116C>A (chr4-88658461-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014606.3(HERC3):c.1116C>A(p.Asp372Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HERC3
NM_014606.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

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:

HERC3 (HGNC:):

HERC3 links:

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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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC3	NM_014606.3 link	c.1116C>A	p.Asp372Glu	missense_variant	Exon 10 of 26	ENST00000402738.6	NP_055421.1	Q15034-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HERC3	ENST00000402738.6 link	c.1116C>A	p.Asp372Glu	missense_variant	Exon 10 of 26	1	NM_014606.3	ENSP00000385684.1	Q15034-1
HERC3	ENST00000264345.7 link	c.1116C>A	p.Asp372Glu	missense_variant	Exon 8 of 24	1			Q15034-1
HERC3	ENST00000512194.2 link	c.1116C>A	p.Asp372Glu	missense_variant	Exon 11 of 26	5		ENSP00000421021.2	H0Y8G9
HERC3	ENST00000470815.1 link	n.194C>A		non_coding_transcript_exon_variant	Exon 1 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453222

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723130

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:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1116C>A (p.D372E) alteration is located in exon 10 (coding exon 8) of the HERC3 gene. This alteration results from a C to A substitution at nucleotide position 1116, causing the aspartic acid (D) at amino acid position 372 to be replaced by a glutamic acid (E). 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

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.93

P;P

Vest4

0.58

MutPred

0.37

Loss of glycosylation at S369 (P = 0.0795);Loss of glycosylation at S369 (P = 0.0795);

MVP

0.79

MPC

0.79

ClinPred

0.97

GERP RS

4.3

Varity_R

0.63

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over