Genetic Variant NM_016323.4:c.2454A>G (chr4-88499935-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_016323.4(HERC5):c.2454A>G(p.Gln818Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,598,852 control chromosomes in the GnomAD database, including 6,540 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.067 ( 461 hom., cov: 33)

Exomes 𝑓: 0.085 ( 6079 hom. )

Consequence

HERC5
NM_016323.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.87

Publications

12 publications found

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:

ENSG00000304354 (HGNC:):

ENSG00000304354 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP7

Synonymous conserved (PhyloP=-1.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC5	NM_016323.4 link	c.2454A>G	p.Gln818Gln	synonymous_variant	Exon 19 of 23	ENST00000264350.8	NP_057407.2	Q9UII4B4DXV3
HERC5	XM_011532022.3 link	c.2229A>G	p.Gln743Gln	synonymous_variant	Exon 17 of 21		XP_011530324.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC5	ENST00000264350.8 link	c.2454A>G	p.Gln818Gln	synonymous_variant	Exon 19 of 23	1	NM_016323.4	ENSP00000264350.3		Q9UII4

Frequencies

GnomAD3 genomes

AF:

0.0675

AC:

10271

AN:

152172

Hom.:

461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0629

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0978

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0756

AC:

18915

AN:

250076

AF XY:

0.0761

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.0558

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.0961

Gnomad OTH exome

AF:

0.0713

GnomAD4 exome

AF:

0.0850

AC:

122977

AN:

1446562

Hom.:

6079

Cov.:

AF XY:

0.0844

AC XY:

60828

AN XY:

720382

show subpopulations

African (AFR)

AF:

0.0123

AC:

410

AN:

33364

American (AMR)

AF:

0.0539

AC:

2403

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

536

AN:

26086

East Asian (EAS)

AF:

0.000429

AC:

AN:

39636

South Asian (SAS)

AF:

0.0622

AC:

5326

AN:

85694

European-Finnish (FIN)

AF:

0.160

AC:

8462

AN:

53024

Middle Eastern (MID)

AF:

0.0348

AC:

199

AN:

5726

European-Non Finnish (NFE)

AF:

0.0921

AC:

101183

AN:

1098542

Other (OTH)

AF:

0.0741

AC:

4441

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

4689

9377

14066

18754

23443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3492

6984

10476

13968

17460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0674

AC:

10267

AN:

152290

Hom.:

461

Cov.:

AF XY:

0.0685

AC XY:

5103

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0163

AC:

679

AN:

41576

American (AMR)

AF:

0.0484

AC:

740

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3468

East Asian (EAS)

AF:

0.00173

AC:

AN:

5194

South Asian (SAS)

AF:

0.0626

AC:

302

AN:

4826

European-Finnish (FIN)

AF:

0.152

AC:

1614

AN:

10596

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0979

AC:

6656

AN:

68016

Other (OTH)

AF:

0.0435

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

485

970

1455

1940

2425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0810

Hom.:

2178

Bravo

AF:

0.0573

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0836

EpiControl

AF:

0.0802

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.054

(source)

DANN

Benign

0.25

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over