1-45011050-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024602.6(HECTD3):c.208G>A(p.Gly70Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,440,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

HECTD3
NM_024602.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11024383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD3	NM_024602.6 linkuse as main transcript	c.208G>A	p.Gly70Ser	missense_variant	1/21	ENST00000372172.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD3	ENST00000372172.5 linkuse as main transcript	c.208G>A	p.Gly70Ser	missense_variant	1/21	5	NM_024602.6	P1	Q5T447-1
UROD	ENST00000652165.1 linkuse as main transcript	c.-1171C>T		5_prime_UTR_variant	1/9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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

GnomAD4 exome

AF:

0.00000233

AC:

AN:

1288328

Hom.:

Cov.:

AF XY:

0.00000317

AC XY:

AN XY:

631136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000394

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000193

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.208G>A (p.G70S) alteration is located in exon 1 (coding exon 1) of the HECTD3 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the glycine (G) at amino acid position 70 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

Cadd

Benign

Dann

Benign

0.92

DEOGEN2

Benign

0.012

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.95

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.19

REVEL

Benign

0.099

Sift

Benign

0.62

Sift4G

Benign

0.96

Polyphen

0.039

Vest4

0.14

MutPred

0.28

Loss of sheet (P = 0.0457);

MVP

0.45

MPC

1.7

ClinPred

0.33

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.15

gMVP

0.41

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