12-112167329-C-A

Position:

• chr12-112167329-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001388303.1(HECTD4):​c.12522G>T​(p.Lys4174Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HECTD4 NM_001388303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD4	NM_001388303.1	c.12522G>T	p.Lys4174Asn	missense_variant	72/76	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4	c.12552G>T	p.Lys4184Asn	missense_variant	72/76		NP_001103132.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1	c.12522G>T	p.Lys4174Asn	missense_variant	72/76		NM_001388303.1	ENSP00000507687.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Aug 07, 2024

The c.12006G>T (p.K4002N) alteration is located in exon 71 (coding exon 70) of the HECTD4 gene. This alteration results from a G to T substitution at nucleotide position 12006, causing the lysine (K) at amino acid position 4002 to be replaced by an asparagine (N). 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	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0050	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0034	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.74	T
REVEL	Benign	0.099
Sift4G	Uncertain	0.035	D;D
Vest4		0.78
MVP		0.043
MPC		0.84
ClinPred		0.89	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1327352129; hg19: chr12-112605133;