12-112163550-A-C

Position:

• chr12-112163550-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001388303.1(HECTD4):​c.12889T>G​(p.Phe4297Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HECTD4 NM_001388303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71

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 1 ACMG points.

• 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.12889T>G	p.Phe4297Val	missense_variant	74/76	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4	c.12919T>G	p.Phe4307Val	missense_variant	74/76		NP_001103132.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1	c.12889T>G	p.Phe4297Val	missense_variant	74/76		NM_001388303.1	ENSP00000507687.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 21 AN: 150834 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00366 AC: 4163 AN: 1137522 Hom.: 0 Cov.: 32 AF XY: 0.00342 AC XY: 1911 AN XY: 558218

Gnomad4 AFR exome AF: 0.00376

Gnomad4 AMR exome AF: 0.000396

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00203

Gnomad4 NFE exome AF: 0.00412

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000139 AC: 21 AN: 150958 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73780

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.000290

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000476

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

Jan 23, 2023

The c.12373T>G (p.F4125V) alteration is located in exon 73 (coding exon 72) of the HECTD4 gene. This alteration results from a T to G substitution at nucleotide position 12373, causing the phenylalanine (F) at amino acid position 4125 to be replaced by a valine (V). 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	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0037	.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0036	T
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
REVEL	Uncertain	0.45
Sift4G	Uncertain	0.015	D;D
Vest4		0.74
MVP		0.043
MPC		1.8
ClinPred		0.95	D
GERP RS		5.6
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2030790673; hg19: chr12-112601354;