NM_014606.3:c.848T>C

Variant names:

• chr4-88655244-T-C
• rs1729753825
• NM_014606.3:c.848T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014606.3(HERC3):​c.848T>C​(p.Val283Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HERC3 NM_014606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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]

HERC3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2585964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC3	NM_014606.3	c.848T>C	p.Val283Ala	missense_variant	Exon 8 of 26	ENST00000402738.6	NP_055421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC3	ENST00000402738.6	c.848T>C	p.Val283Ala	missense_variant	Exon 8 of 26	1	NM_014606.3	ENSP00000385684.1
HERC3	ENST00000264345.7	c.848T>C	p.Val283Ala	missense_variant	Exon 6 of 24	1
HERC3	ENST00000512194.2	c.848T>C	p.Val283Ala	missense_variant	Exon 9 of 26	5		ENSP00000421021.2
HERC3	ENST00000407637.5	c.848T>C	p.Val283Ala	missense_variant	Exon 8 of 9	1		ENSP00000384005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.848T>C (p.V283A) alteration is located in exon 8 (coding exon 6) of the HERC3 gene. This alteration results from a T to C substitution at nucleotide position 848, causing the valine (V) at amino acid position 283 to be replaced by an alanine (A). 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	0.21
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.065	N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.056	T;D;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.037	B;.;B
Vest4		0.48
MutPred		0.34		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.48
MPC		1.2
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs1729753825; hg19: chr4-89576395;