Variant 4-88468404-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016323.4(HERC5):c.1116G>C(p.Leu372Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,610,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

HERC5
NM_016323.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Variant links:

Genes affected

HERC5 (HGNC:24368): (HECT and RLD domain containing E3 ubiquitin protein ligase 5) This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells. The protein localizes to the cytoplasm and perinuclear region and functions as an interferon-induced E3 protein ligase that mediates ISGylation of protein targets. The protein also acts as a modulator of the antiviral immune response. The gene lies in a cluster of HERC family genes on chromosome 4. [provided by RefSeq, Aug 2021]

HERC5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02377069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC5	NM_016323.4 linkuse as main transcript	c.1116G>C	p.Leu372Phe	missense_variant	8/23	ENST00000264350.8
HERC5	XM_011532022.3 linkuse as main transcript	c.1116G>C	p.Leu372Phe	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC5	ENST00000264350.8 linkuse as main transcript	c.1116G>C	p.Leu372Phe	missense_variant	8/23	1	NM_016323.4	P1
HERC5	ENST00000508159.1 linkuse as main transcript	c.30G>C	p.Leu10Phe	missense_variant	2/17	2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000445

AC:

111

AN:

249628

Hom.:

AF XY:

0.000445

AC XY:

AN XY:

134960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000940

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000618

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000211

AC:

307

AN:

1458140

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

725512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000764

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000197

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000618

AC:

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

Feb 16, 2023

The c.1116G>C (p.L372F) alteration is located in exon 8 (coding exon 8) of the HERC5 gene. This alteration results from a G to C substitution at nucleotide position 1116, causing the leucine (L) at amino acid position 372 to be replaced by a phenylalanine (F). 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

0.20

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

0.19

N;N

REVEL

Benign

0.054

Sift

Benign

0.54

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0050

B;.

Vest4

0.35

MutPred

0.54

Loss of catalytic residue at L372 (P = 0.0082);.;

MVP

0.27

MPC

0.68

ClinPred

0.033

GERP RS

2.3

Varity_R

0.023

gMVP

0.48

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

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