10-68014084-G-T

Variant names:

• chr10-68014084-G-T
• rs866255
• NM_015601.4:c.1011C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015601.4(HERC4):​c.1011C>A​(p.Ser337Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HERC4 NM_015601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 25 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC4	NM_015601.4	c.1011C>A	p.Ser337Arg	missense_variant	Exon 9 of 25	ENST00000373700.9	NP_056416.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC4	ENST00000373700.9	c.1011C>A	p.Ser337Arg	missense_variant	Exon 9 of 25	1	NM_015601.4	ENSP00000362804.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 14836

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.4	.;L;L;L
PhyloP100		1.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.039	D;D;D;D
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.99, 0.96, 0.89	.;D;D;P
Vest4		0.76
MutPred		0.25		.;Gain of MoRF binding (P = 0.0522);Gain of MoRF binding (P = 0.0522);Gain of MoRF binding (P = 0.0522);
MVP		0.81
MPC		1.9
ClinPred		0.97	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.70
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs866255; hg19: chr10-69773841;