4-88463975-G-A

Position:

• chr4-88463975-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016323.4(HERC5):​c.901G>A​(p.Ala301Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00361 in 1,612,664 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (96 hom.)
• Consequence: HERC5 NM_016323.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.83

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]

LOC102723458 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013751119).
• BP6: Variant 4-88463975-G-A is Benign according to our data. Variant chr4-88463975-G-A is described in ClinVar as [Benign]. Clinvar id is 780486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC5	NM_016323.4	c.901G>A	p.Ala301Thr	missense_variant	6/23	ENST00000264350.8	NP_057407.2
HERC5	XM_011532022.3	c.901G>A	p.Ala301Thr	missense_variant	6/21		XP_011530324.3
LOC102723458	XR_938972.3	n.19+3656C>T		intron_variant
LOC102723458	XR_938976.3	n.76+3656C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC5	ENST00000264350.8	c.901G>A	p.Ala301Thr	missense_variant	6/23	1	NM_016323.4	ENSP00000264350.3

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2976 AN: 151750 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00454

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0135

GnomAD3 exomes AF: 0.00530 AC: 1330 AN: 250896 Hom.: 42 AF XY: 0.00375 AC XY: 508 AN XY: 135624

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00194 AC: 2835 AN: 1460796 Hom.: 96 Cov.: 31 AF XY: 0.00166 AC XY: 1203 AN XY: 726696

Gnomad4 AFR exome AF: 0.0707

Gnomad4 AMR exome AF: 0.00325

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.0197 AC: 2987 AN: 151868 Hom.: 93 Cov.: 32 AF XY: 0.0194 AC XY: 1443 AN XY: 74220

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.00454

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00409 Hom.: 29

Bravo AF: 0.0223

ESP6500AA AF: 0.0699 AC: 308

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00661 AC: 802

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.97	D
Vest4		0.55
MVP		0.94
MPC		0.60
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.51

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

Other links and lift over

dbSNP: rs17014143; hg19: chr4-89385126;