chr4-88408556-A-T

Variant names:

• chr4-88408556-A-T
• rs571683231
• NM_017912.4:c.1307A>T

Variant summary

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

The NM_017912.4(HERC6):​c.1307A>T​(p.Asp436Val) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D436G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HERC6 NM_017912.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 1 publications found

Genes affected

HERC6 (HGNC:26072): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 6) HERC6 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, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC6	NM_017912.4	c.1307A>T	p.Asp436Val	missense_variant	Exon 11 of 23	ENST00000264346.12	NP_060382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC6	ENST00000264346.12	c.1307A>T	p.Asp436Val	missense_variant	Exon 11 of 23	1	NM_017912.4	ENSP00000264346.8
HERC6	ENST00000380265.9	c.1307A>T	p.Asp436Val	missense_variant	Exon 11 of 22	1		ENSP00000369617.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.0086
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;D
Vest4		0.66
MutPred		0.55		Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);
MVP		0.82
MPC		0.69
ClinPred		1.0	D
GERP RS		0.51
Varity_R		0.71
gMVP		0.60
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs571683231; hg19: chr4-89329708;