chr12-112167507-G-A

Variant summary

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

The NM_001388303.1(HECTD4):​c.12344C>T​(p.Thr4115Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000467 in 1,607,136 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 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

HECTD4
NM_001388303.1 missense

Scores

8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94
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 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=0.15742168).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HECTD4NM_001388303.1 linkuse as main transcriptc.12344C>T p.Thr4115Ile missense_variant 72/76 ENST00000682272.1 NP_001375232.1
HECTD4NM_001109662.4 linkuse as main transcriptc.12374C>T p.Thr4125Ile missense_variant 72/76 NP_001103132.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HECTD4ENST00000682272.1 linkuse as main transcriptc.12344C>T p.Thr4115Ile missense_variant 72/76 NM_001388303.1 ENSP00000507687 P4

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
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:
0.0000147
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.0000164
AC:
4
AN:
243642
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
132280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000340
GnomAD4 exome
AF:
0.0000302
AC:
44
AN:
1454888
Hom.:
0
Cov.:
31
AF XY:
0.0000291
AC XY:
21
AN XY:
722860
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000152
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.000583
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00287
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.000110
ExAC
AF:
0.0000496
AC:
6
Asia WGS
AF:
0.00173
AC:
6
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 GeneticsJan 09, 2024The c.11828C>T (p.T3943I) alteration is located in exon 71 (coding exon 70) of the HECTD4 gene. This alteration results from a C to T substitution at nucleotide position 11828, causing the threonine (T) at amino acid position 3943 to be replaced by an isoleucine (I). 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
-0.046
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.030
.;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.71
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.73
T
REVEL
Benign
0.16
Sift4G
Uncertain
0.0030
D;D
Vest4
0.45
MVP
0.043
MPC
1.1
ClinPred
0.55
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.63

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: rs376919176; hg19: chr12-112605311; COSMIC: COSV66398945; COSMIC: COSV66398945; API