12-112167887-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001388303.1(HECTD4):c.12239T>C(p.Val4080Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: HECTD4 NM_001388303.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HECTD4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD4	NM_001388303.1	c.12239T>C	p.Val4080Ala	missense_variant	71/76	ENST00000682272.1
HECTD4	NM_001109662.4	c.12269T>C	p.Val4090Ala	missense_variant	71/76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD4	ENST00000682272.1	c.12239T>C	p.Val4080Ala	missense_variant	71/76		NM_001388303.1	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 151990 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3 AN: 151990 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

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 17, 2022

The c.11723T>C (p.V3908A) alteration is located in exon 70 (coding exon 69) of the HECTD4 gene. This alteration results from a T to C substitution at nucleotide position 11723, causing the valine (V) at amino acid position 3908 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	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
REVEL	Uncertain	0.38
Sift4G	Uncertain	0.010	D;D
Vest4		0.88
MVP		0.043
MPC		1.1
ClinPred		0.82	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs768972756; hg19: chr12-112605691;