Genetic Variant HECTD3:p.Glu738Asp (chr1-45004306-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024602.6(HECTD3):c.2214G>C(p.Glu738Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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

HECTD3
NM_024602.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.427

Publications

0 publications found

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:

ENSG00000300507 (HGNC:):

ENSG00000300507 links:

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ACMG classification

Classification was made for transcript

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, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024602.6. 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
	HECTD3	NM_024602.6	MANE Select	c.2214G>C	p.Glu738Asp	missense	Exon 17 of 21	NP_078878.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HECTD3	ENST00000372172.5	TSL:5 MANE Select	c.2214G>C	p.Glu738Asp	missense	Exon 17 of 21	ENSP00000361245.4	Q5T447-1
HECTD3	ENST00000486132.5	TSL:1	n.1061G>C		non_coding_transcript_exon	Exon 2 of 6
HECTD3	ENST00000875142.1		c.2355G>C	p.Glu785Asp	missense	Exon 17 of 21	ENSP00000545201.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111886

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

PhyloP100

0.43

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.35

Sift

Benign

0.11

Sift4G

Benign

0.25

Polyphen

0.099

Vest4

0.78

MutPred

0.80

Gain of ubiquitination at K741 (P = 0.1215)

MVP

0.47

MPC

0.87

ClinPred

0.79

GERP RS

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.81

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over