12-112167318-C-G

Position:

• chr12-112167318-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001388303.1(HECTD4):​c.12533G>C​(p.Ser4178Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HECTD4 NM_001388303.1 missense, splice_region
• Scores: Splicing: ADA: 0.002381
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.56

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]

ACMG classification

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=0.18715206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD4	NM_001388303.1	c.12533G>C	p.Ser4178Thr	missense_variant, splice_region_variant	72/76	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4	c.12563G>C	p.Ser4188Thr	missense_variant, splice_region_variant	72/76		NP_001103132.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1	c.12533G>C	p.Ser4178Thr	missense_variant, splice_region_variant	72/76		NM_001388303.1	ENSP00000507687	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

HECTD4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

The HECTD4 c.12131G>C variant is predicted to result in the amino acid substitution p.Ser4044Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.0032	.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.53	N;N;N;N
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.072
Sift4G	Benign	0.29	T;T
Vest4		0.49
MVP		0.068
MPC		0.59
ClinPred		0.19	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.012
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112605122;