12-112167329-C-A

Variant names:

• chr12-112167329-C-A
• rs1327352129
• NM_001388303.1:c.12522G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. 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: 1.92
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Broad Center for Mendelian Genomics, G2P, Ambry Genetics, Baylor College of Medicine Research Center, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388303.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECTD4	NM_001388303.1	MANE Select	c.12522G>T	p.Lys4174Asn	missense	Exon 72 of 76	NP_001375232.1	A0A804HJX8
	HECTD4	NM_001109662.4		c.12552G>T	p.Lys4184Asn	missense	Exon 72 of 76	NP_001103132.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECTD4	ENST00000682272.1	MANE Select	c.12522G>T	p.Lys4174Asn	missense	Exon 72 of 76	ENSP00000507687.1	A0A804HJX8
	HECTD4	ENST00000377560.9	TSL:5	c.12516G>T	p.Lys4172Asn	missense	Exon 72 of 76	ENSP00000366783.7	J3KPF0
	HECTD4	ENST00000550722.5	TSL:5	c.12120G>T	p.Lys4040Asn	missense	Exon 72 of 76	ENSP00000449784.2	F8VWT9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
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
M_CAP	Benign	0.0034	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.92	T
PhyloP100		1.9
PrimateAI	Uncertain	0.74	T
REVEL	Benign	0.099
Sift4G	Uncertain	0.035	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
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1327352129; hg19: chr12-112605133;