4-88667397-C-T

Variant names:

• chr4-88667397-C-T
• rs1486123639
• NM_014606.3:c.1352C>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>T​(p.Thr451Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000313 in 1,599,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HERC3 NM_014606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>T	p.Thr451Met	missense	Exon 13 of 26	NP_055421.1	Q15034-1
	HERC3	NM_001375480.1		c.1352C>T	p.Thr451Met	missense	Exon 13 of 26	NP_001362409.1
	HERC3	NM_001375478.1		c.1352C>T	p.Thr451Met	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>T	p.Thr451Met	missense	Exon 13 of 26	ENSP00000385684.1	Q15034-1
	HERC3	ENST00000512194.2	TSL:5	c.1352C>T	p.Thr451Met	missense	Exon 14 of 26	ENSP00000421021.2	H0Y8G9
	HERC3	ENST00000950980.1		c.1355C>T	p.Thr452Met	missense	Exon 13 of 26	ENSP00000621039.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000828 AC: 2 AN: 241446 AF XY: 0.0000154

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447326 Hom.: 0 Cov.: 27 AF XY: 0.00000417 AC XY: 3 AN XY: 719976

African (AFR) AF: 0.0000305 AC: 1 AN: 32790

American (AMR) AF: 0.00 AC: 0 AN: 42694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 83704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5386

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104576

Other (OTH) AF: 0.0000167 AC: 1 AN: 59738

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

African (AFR) AF: 0.0000483 AC: 2 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.20
Sift	Benign	0.057	T
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.33		Loss of methylation at K450 (P = 0.0306)
MVP		0.31
MPC		1.5
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.58
Mutation Taster		=52/48	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: rs1486123639; hg19: chr4-89588548; COSMIC: COSV52024825; COSMIC: COSV52024825;