dbSNP rs955926823: HERC5:p.Met208Val (chr4-88462290-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016323.4(HERC5):c.622A>G(p.Met208Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M208L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HERC5
NM_016323.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.098504245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC5	NM_016323.4 link	c.622A>G	p.Met208Val	missense_variant	Exon 4 of 23	ENST00000264350.8	NP_057407.2	Q9UII4B4DXV3
HERC5	XM_011532022.3 link	c.622A>G	p.Met208Val	missense_variant	Exon 4 of 21		XP_011530324.3
LOC102723458	XR_938972.3 link	n.19+5341T>C		intron_variant	Intron 1 of 5
LOC102723458	XR_938976.3 link	n.76+5341T>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HERC5	ENST00000264350.8 link	c.622A>G	p.Met208Val	missense_variant	Exon 4 of 23	1	NM_016323.4	ENSP00000264350.3	Q9UII4
ENSG00000304354	ENST00000802705.1 link	n.524-41862T>C		intron_variant	Intron 1 of 3
HERC5	ENST00000508695.1 link	n.*27A>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.024

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.59

M_CAP

Benign

0.016

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Uncertain

0.029

Sift4G

Benign

0.12

Polyphen

0.058

Vest4

0.14

MutPred

0.35

Loss of glycosylation at S209 (P = 0.0617);

MVP

0.67

MPC

0.16

ClinPred

0.42

GERP RS

1.8

Varity_R

0.22

gMVP

0.77

Mutation Taster

=93/7

polymorphism

(source)

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

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rs955926823

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over