rs1486123639

Variant names:

• chr4-88667397-C-A
• rs1486123639
• NM_014606.3:c.1352C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-88667397-C-A
• chr4-88667397-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014606.3(HERC3):​c.1352C>A​(p.Thr451Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T451M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HERC3 NM_014606.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22
• Publications: 3 publications found

Genes affected

HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC3	NM_014606.3	MANE Select	c.1352C>A	p.Thr451Lys	missense	Exon 13 of 26	NP_055421.1	Q15034-1
	HERC3	NM_001375480.1		c.1352C>A	p.Thr451Lys	missense	Exon 13 of 26	NP_001362409.1
	HERC3	NM_001375478.1		c.1352C>A	p.Thr451Lys	missense	Exon 13 of 25	NP_001362407.1	H0Y8G9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC3	ENST00000402738.6	TSL:1 MANE Select	c.1352C>A	p.Thr451Lys	missense	Exon 13 of 26	ENSP00000385684.1	Q15034-1
	HERC3	ENST00000512194.2	TSL:5	c.1352C>A	p.Thr451Lys	missense	Exon 14 of 26	ENSP00000421021.2	H0Y8G9
	HERC3	ENST00000950980.1		c.1355C>A	p.Thr452Lys	missense	Exon 13 of 26	ENSP00000621039.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.27
Sift	Benign	0.061	T
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.43		Loss of ubiquitination at K450 (P = 0.0246)
MVP		0.40
MPC		1.7
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.51
gMVP		0.74
Mutation Taster		=43/57	disease causing

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: rs1486123639; hg19: chr4-89588548;