10-67966786-C-T

Position:

• chr10-67966786-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015601.4(HERC4):​c.1823G>A​(p.Gly608Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HERC4 NM_015601.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21

Genes affected

HERC4 (HGNC:24521): (HECT and RLD domain containing E3 ubiquitin protein ligase 4) HERC4 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).[supplied by OMIM, Mar 2008]

HERC4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35010248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC4	NM_015601.4	c.1823G>A	p.Gly608Glu	missense_variant	16/25	ENST00000373700.9	NP_056416.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC4	ENST00000373700.9	c.1823G>A	p.Gly608Glu	missense_variant	16/25	1	NM_015601.4	ENSP00000362804.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

The c.1823G>A (p.G608E) alteration is located in exon 16 (coding exon 14) of the HERC4 gene. This alteration results from a G to A substitution at nucleotide position 1823, causing the glycine (G) at amino acid position 608 to be replaced by a glutamic acid (E). 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	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.24	.;.;T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	.;L;L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.17	B;D;B;B
Vest4		0.54
MutPred		0.46		.;Loss of ubiquitination at K606 (P = 0.079);Loss of ubiquitination at K606 (P = 0.079);Loss of ubiquitination at K606 (P = 0.079);
MVP		0.69
MPC		1.0
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-69726543;