12-112167501-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.12350G>C(p.Gly4117Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HECTD4 NM_001388303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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 where missense usually causes diseases, HECTD4
• BP4: Computational evidence support a benign effect (MetaRNN=0.109305024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD4	NM_001388303.1	c.12350G>C	p.Gly4117Ala	missense_variant	72/76	ENST00000682272.1
HECTD4	NM_001109662.4	c.12380G>C	p.Gly4127Ala	missense_variant	72/76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD4	ENST00000682272.1	c.12350G>C	p.Gly4117Ala	missense_variant	72/76		NM_001388303.1	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.11834G>C (p.G3945A) alteration is located in exon 71 (coding exon 70) of the HECTD4 gene. This alteration results from a G to C substitution at nucleotide position 11834, causing the glycine (G) at amino acid position 3945 to be replaced by an alanine (A). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.25
Eigen	Benign	-0.17
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.00056	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.78	D;D;D;D
PrimateAI	Uncertain	0.66	T
REVEL	Benign	0.055
Sift4G	Benign	0.87	T;T
Vest4		0.21
MVP		0.043
MPC		0.69
ClinPred		0.32	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112605305;