12-112163550-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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HECTD4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD4	NM_001388303.1	c.12889T>G	p.Phe4297Val	missense_variant	74/76	ENST00000682272.1
HECTD4	NM_001109662.4	c.12919T>G	p.Phe4307Val	missense_variant	74/76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD4	ENST00000682272.1	c.12889T>G	p.Phe4297Val	missense_variant	74/76		NM_001388303.1	P4

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
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;