Genetic Variant HECTD3:p.Leu10Pro (chr1-45011229-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024602.6(HECTD3):c.29T>C(p.Leu10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000807 in 1,239,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L10Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

HECTD3
NM_024602.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.915

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:

UROD (HGNC:12591): (uroporphyrinogen decarboxylase) This gene encodes an enzyme in the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains. Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoetic porphyria.[provided by RefSeq, Aug 2010]

UROD Gene-Disease associations (from GenCC):

UROD-related inherited porphyria
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
familial porphyria cutanea tarda
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hepatoerythropoietic porphyria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UROD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22230521).

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.29T>C	p.Leu10Pro	missense	Exon 1 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.29T>C	p.Leu10Pro	missense	Exon 1 of 21	ENSP00000361245.4	Q5T447-1
HECTD3	ENST00000875142.1		c.29T>C	p.Leu10Pro	missense	Exon 1 of 21	ENSP00000545201.1
HECTD3	ENST00000875144.1		c.29T>C	p.Leu10Pro	missense	Exon 1 of 21	ENSP00000545203.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.07e-7

AC:

AN:

1239460

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

603214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24318

American (AMR)

AF:

0.00

AC:

AN:

13018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17692

East Asian (EAS)

AF:

0.00

AC:

AN:

28224

South Asian (SAS)

AF:

0.00

AC:

AN:

57650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3626

European-Non Finnish (NFE)

AF:

9.86e-7

AC:

AN:

1013834

Other (OTH)

AF:

0.00

AC:

AN:

51280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.92

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.016

Polyphen

0.0

Vest4

0.58

MutPred

0.18

Gain of loop (P = 0.0121)

MVP

0.47

MPC

2.4

ClinPred

0.20

GERP RS

2.9

PromoterAI

0.017

Neutral

(source)

Varity_R

0.33

gMVP

0.54

Mutation Taster

=77/23

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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