Variant 1-45011223-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_024602.6(HECTD3):c.35C>T(p.Ser12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,420,010 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 3 hom. )

Consequence

HECTD3
NM_024602.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity HECD3_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.007984042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD3	NM_024602.6 linkuse as main transcript	c.35C>T	p.Ser12Phe	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.35C>T	p.Ser12Phe	missense_variant	1/21	5	NM_024602.6	P1	Q5T447-1
UROD	ENST00000652165.1 linkuse as main transcript	c.-998G>A		5_prime_UTR_variant	1/9

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

297

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00203

AC:

AN:

30032

Hom.:

AF XY:

0.00224

AC XY:

AN XY:

16978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.000562

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00251

AC:

3177

AN:

1267690

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1582

AN XY:

619608

show subpopulations

Gnomad4 AFR exome

AF:

0.000199

Gnomad4 AMR exome

AF:

0.00113

Gnomad4 ASJ exome

AF:

0.000315

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00197

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00284

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00195

AC:

297

AN:

152320

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00363

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00250

Hom.:

Bravo

AF:

0.00184

ExAC

AF:

0.000765

AC:

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

Jun 11, 2021

The c.35C>T (p.S12F) alteration is located in exon 1 (coding exon 1) of the HECTD3 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the serine (S) at amino acid position 12 to be replaced by a phenylalanine (F). 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

0.33

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Benign

0.054

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.92

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.7

REVEL

Benign

0.14

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Polyphen

0.70

Vest4

0.42

MVP

0.64

MPC

2.4

ClinPred

0.091

GERP RS

4.0

Varity_R

0.20

gMVP

0.30

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