Genetic Variant HECTD3:p.Ala816Thr (chr1-45003724-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_024602.6(HECTD3):c.2446G>A(p.Ala816Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

HECTD3
NM_024602.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

HECTD3 (HGNC:26117): (HECT domain E3 ubiquitin protein ligase 3) The protein encoded by this gene transfers ubiquitin from an E2 ubiquitin-conjugating enzyme to targeted substrates, leading to the degradation of those substrates. The encoded protein has been shown to transfer ubiquitin to TRIOBP to facilitate cell cycle progression, and to STX8. [provided by RefSeq, Dec 2012]

HECTD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015256733).

BP6

Variant 1-45003724-C-T is Benign according to our data. Variant chr1-45003724-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 757624.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD3	NM_024602.6 link	c.2446G>A	p.Ala816Thr	missense_variant	Exon 20 of 21	ENST00000372172.5	NP_078878.3	Q5T447-1A1A4G1B3KU34
HECTD3	XM_047430487.1 link	c.1594G>A	p.Ala532Thr	missense_variant	Exon 18 of 19		XP_047286443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HECTD3	ENST00000372172.5 link	c.2446G>A	p.Ala816Thr	missense_variant	Exon 20 of 21	5	NM_024602.6	ENSP00000361245.4	Q5T447-1
HECTD3	ENST00000486132.5 link	n.1293G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
HECTD3	ENST00000372168.7 link	c.1276G>A	p.Ala426Thr	missense_variant	Exon 12 of 13	2		ENSP00000361241.3	Q5T447-2
HECTD3	ENST00000486296.5 link	n.*131G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00234

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000309

AC:

AN:

249548

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00389

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00453

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000118

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00234

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000339

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

.;L

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.11

Sift

Benign

0.22

T;T

Sift4G

Benign

0.17

T;D

Polyphen

0.90

P;P

Vest4

0.58

MVP

0.71

MPC

0.46

ClinPred

0.048

GERP RS

5.7

Varity_R

0.038

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over