Variant 12-112164124-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001388303.1(HECTD4):c.12686G>A(p.Arg4229Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,600,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

HECTD4
NM_001388303.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Variant links:

Genes affected

HECTD4 (HGNC:26611): (HECT domain E3 ubiquitin protein ligase 4) Predicted to enable ubiquitin-protein transferase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

HECTD4 links:

HECTD4 (HGNC:):

HECTD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HECTD4. . Gene score misZ 6.9421 (greater than the threshold 3.09). Trascript score misZ 8.6089 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum.

BP4

Computational evidence support a benign effect (MetaRNN=0.16764131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD4	NM_001388303.1 linkuse as main transcript	c.12686G>A	p.Arg4229Gln	missense_variant	73/76	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4 linkuse as main transcript	c.12716G>A	p.Arg4239Gln	missense_variant	73/76		NP_001103132.4	F8VWT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1 linkuse as main transcript	c.12686G>A	p.Arg4229Gln	missense_variant	73/76		NM_001388303.1	ENSP00000507687.1		A0A804HJX8

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000187

AC:

AN:

235436

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

128602

show subpopulations

Gnomad AFR exome

AF:

0.0000682

Gnomad AMR exome

AF:

0.0000902

Gnomad ASJ exome

AF:

0.000313

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000339

Gnomad FIN exome

AF:

0.0000496

Gnomad NFE exome

AF:

0.000324

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.000206

AC:

298

AN:

1448046

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

144

AN XY:

719152

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.000467

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.000168

GnomAD4 genome

AF:

0.000151

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.000190

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

Aug 02, 2023

The c.12170G>A (p.R4057Q) alteration is located in exon 72 (coding exon 71) of the HECTD4 gene. This alteration results from a G to A substitution at nucleotide position 12170, causing the arginine (R) at amino acid position 4057 to be replaced by a glutamine (Q). 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

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.010

.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.0087

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.39

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.55

REVEL

Benign

0.19

Sift4G

Uncertain

0.016

D;D

Vest4

0.39

MVP

0.12

MPC

1.7

ClinPred

0.55

GERP RS

5.2

gMVP

0.52

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