rs10516809

Positions:

• chr4-88499935-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_016323.4(HERC5):​c.2454A>G​(p.Gln818=) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
HERC5	NM_016323.4	c.2454A>G	p.Gln818=	synonymous_variant	19/23	ENST00000264350.8	NP_057407.2
HERC5	XM_011532022.3	c.2229A>G	p.Gln743=	synonymous_variant	17/21		XP_011530324.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC5	ENST00000264350.8	c.2454A>G	p.Gln818=	synonymous_variant	19/23	1	NM_016323.4	ENSP00000264350	P1
HERC5	ENST00000508159.1	c.1368A>G	p.Gln456=	synonymous_variant	13/17	2		ENSP00000424129
HERC5	ENST00000502913.1	n.1175A>G		non_coding_transcript_exon_variant	9/12	2
HERC5	ENST00000510223.5	n.1942A>G		non_coding_transcript_exon_variant	9/12	2

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10271 AN: 152172 Hom.: 461 Cov.: 33

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

GnomAD3 exomes AF: 0.0756 AC: 18915 AN: 250076 Hom.: 1005 AF XY: 0.0761 AC XY: 10293 AN XY: 135270

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 SAS exome AF: 0.0611

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.: 28 AF XY: 0.0844 AC XY: 60828 AN XY: 720382

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0539

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.0622

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.0921

Gnomad4 OTH exome AF: 0.0741

GnomAD4 genome AF: 0.0674 AC: 10267 AN: 152290 Hom.: 461 Cov.: 33 AF XY: 0.0685 AC XY: 5103 AN XY: 74460

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0484

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0626

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.0979

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0832 Hom.: 1506

Bravo AF: 0.0573

Asia WGS AF: 0.0230 AC: 81 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
DANN	Benign	0.25

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

LitVar

Other links and lift over

dbSNP: rs10516809; hg19: chr4-89421086;