10-91493483-A-G

Position:

• chr10-91493483-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182765.6(HECTD2):​c.1496A>G​(p.Tyr499Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HECTD2 NM_182765.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

HECTD2 (HGNC:26736): (HECT domain E3 ubiquitin protein ligase 2) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in protein ubiquitination. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HECTD2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33674634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD2	NM_182765.6	c.1496A>G	p.Tyr499Cys	missense_variant	14/21	ENST00000298068.10	NP_877497.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD2	ENST00000298068.10	c.1496A>G	p.Tyr499Cys	missense_variant	14/21	1	NM_182765.6	ENSP00000298068.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401806 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 696440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 29, 2024

The c.1496A>G (p.Y499C) alteration is located in exon 14 (coding exon 14) of the HECTD2 gene. This alteration results from a A to G substitution at nucleotide position 1496, causing the tyrosine (Y) at amino acid position 499 to be replaced by a cysteine (C). 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	.;L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.49
MutPred		0.57		Loss of ubiquitination at K499 (P = 0.0935);.;.;
MVP		0.45
MPC		2.6
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-93253240;