12-112163651-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001388303.1(HECTD4):​c.12788G>A​(p.Arg4263Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,540,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HECTD4
NM_001388303.1 missense

Scores

5
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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=0.024242133).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HECTD4NM_001388303.1 linkuse as main transcriptc.12788G>A p.Arg4263Gln missense_variant 74/76 ENST00000682272.1 NP_001375232.1
HECTD4NM_001109662.4 linkuse as main transcriptc.12818G>A p.Arg4273Gln missense_variant 74/76 NP_001103132.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HECTD4ENST00000682272.1 linkuse as main transcriptc.12788G>A p.Arg4263Gln missense_variant 74/76 NM_001388303.1 ENSP00000507687 P4

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152222
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00255
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:
0.000265
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000308
AC:
44
AN:
142882
Hom.:
0
AF XY:
0.000275
AC XY:
21
AN XY:
76424
show subpopulations
Gnomad AFR exome
AF:
0.000137
Gnomad AMR exome
AF:
0.00142
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000996
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000131
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000155
AC:
215
AN:
1388628
Hom.:
0
Cov.:
33
AF XY:
0.000152
AC XY:
104
AN XY:
684690
show subpopulations
Gnomad4 AFR exome
AF:
0.0000641
Gnomad4 AMR exome
AF:
0.00139
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000567
Gnomad4 SAS exome
AF:
0.0000256
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000143
Gnomad4 OTH exome
AF:
0.000122
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152340
Hom.:
1
Cov.:
32
AF XY:
0.000456
AC XY:
34
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00255
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000177
Hom.:
0
Bravo
AF:
0.000314
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000160
AC:
1
ExAC
AF:
0.0000977
AC:
3
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

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 submitterclinical testingAmbry GeneticsDec 05, 2022The c.12272G>A (p.R4091Q) alteration is located in exon 73 (coding exon 72) of the HECTD4 gene. This alteration results from a G to A substitution at nucleotide position 12272, causing the arginine (R) at amino acid position 4091 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
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.014
.;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.024
T;T
MetaSVM
Benign
-0.72
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.73
T
REVEL
Uncertain
0.43
Sift4G
Benign
0.18
T;T
Vest4
0.88
MVP
0.40
MPC
1.2
ClinPred
0.36
T
GERP RS
5.7
gMVP
0.81

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.

Other links and lift over

dbSNP: rs181634938; hg19: chr12-112601455; COSMIC: COSV66394904; COSMIC: COSV66394904; API