1-45004786-C-A

Position:

• chr1-45004786-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024602.6(HECTD3):​c.1956G>T​(p.Met652Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HECTD3 NM_024602.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

HECTD3 (HGNC:26117): (HECT domain E3 ubiquitin protein ligase 3) The protein encoded by this gene transfers ubiquitin from an E2 ubiquitin-conjugating enzyme to targeted substrates, leading to the degradation of those substrates. The encoded protein has been shown to transfer ubiquitin to TRIOBP to facilitate cell cycle progression, and to STX8. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD3	NM_024602.6	c.1956G>T	p.Met652Ile	missense_variant	16/21	ENST00000372172.5
HECTD3	XM_047430487.1	c.1104G>T	p.Met368Ile	missense_variant	14/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD3	ENST00000372172.5	c.1956G>T	p.Met652Ile	missense_variant	16/21	5	NM_024602.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 14, 2023

The c.1956G>T (p.M652I) alteration is located in exon 16 (coding exon 16) of the HECTD3 gene. This alteration results from a G to T substitution at nucleotide position 1956, causing the methionine (M) at amino acid position 652 to be replaced by an isoleucine (I). 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.72
Eigen	Benign	-0.22
Eigen_PC	Benign	0.026
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.18
Sift	Benign	0.40	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0040	B;B
Vest4		0.75
MutPred		0.53		.;Loss of disorder (P = 0.0565);
MVP		0.56
MPC		0.50
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.22
gMVP		0.78

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: rs1286083240; hg19: chr1-45470458;