Variant 4-88457459-G-A 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.190G>A(p.Ala64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,345,096 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

HERC5
NM_016323.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.954

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:

LOC102723458 (HGNC:):

LOC102723458 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=0.02963823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HERC5	NM_016323.4 linkuse as main transcript	c.190G>A	p.Ala64Thr	missense_variant	1/23	ENST00000264350.8
HERC5	XM_011532022.3 linkuse as main transcript	c.190G>A	p.Ala64Thr	missense_variant	1/21
LOC102723458	XR_938972.3 linkuse as main transcript	n.19+10172C>T		intron_variant, non_coding_transcript_variant
LOC102723458	XR_938976.3 linkuse as main transcript	n.76+10172C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC5	ENST00000264350.8 linkuse as main transcript	c.190G>A	p.Ala64Thr	missense_variant	1/23	1	NM_016323.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.000500

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000344

AC:

AN:

52322

Hom.:

AF XY:

0.000467

AC XY:

AN XY:

29960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000543

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000416

AC:

496

AN:

1192830

Hom.:

Cov.:

AF XY:

0.000428

AC XY:

248

AN XY:

578856

show subpopulations

Gnomad4 AFR exome

AF:

0.0000402

Gnomad4 AMR exome

AF:

0.000854

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000878

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000461

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.000407

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000264

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

Jul 06, 2021

The c.190G>A (p.A64T) alteration is located in exon 1 (coding exon 1) of the HERC5 gene. This alteration results from a G to A substitution at nucleotide position 190, causing the alanine (A) at amino acid position 64 to be replaced by a threonine (T). 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

0.16

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.78

M_CAP

Benign

0.025

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.77

REVEL

Benign

0.055

Sift

Benign

0.14

Sift4G

Benign

0.27

Polyphen

0.12

Vest4

0.18

MutPred

0.45

Loss of sheet (P = 0.0228);

MVP

0.33

MPC

1.7

ClinPred

0.096

GERP RS

1.6

Varity_R

0.059

gMVP

0.14

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