chr14-31107170-A-C

Position:

• chr14-31107170-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015382.4(HECTD1):​c.6702T>G​(p.Asp2234Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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: 0.0000014 (0 hom.)
• Consequence: HECTD1 NM_015382.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.439

Genes affected

HECTD1 (HGNC:20157): (HECT domain E3 ubiquitin protein ligase 1) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in anatomical structure development; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; and protein K63-linked ubiquitination. Predicted to act upstream of or within several processes, including animal organ development; negative regulation of protein localization to plasma membrane; and protein autoubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

HECTD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25216708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD1	NM_015382.4	c.6702T>G	p.Asp2234Glu	missense_variant	38/43	ENST00000399332.6	NP_056197.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD1	ENST00000399332.6	c.6702T>G	p.Asp2234Glu	missense_variant	38/43	5	NM_015382.4	ENSP00000382269.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248514 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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

Dec 03, 2024

The c.6702T>G (p.D2234E) alteration is located in exon 38 (coding exon 37) of the HECTD1 gene. This alteration results from a T to G substitution at nucleotide position 6702, causing the aspartic acid (D) at amino acid position 2234 to be replaced by a glutamic acid (E). 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	0.33
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.92	D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.18	.;T;T
Sift4G	Benign	0.18	T;T;T
Vest4		0.43
MutPred		0.34		.;Gain of catalytic residue at A2229 (P = 0.0082);Gain of catalytic residue at A2229 (P = 0.0082);
MVP		0.70
MPC		1.3
ClinPred		0.92	D
GERP RS		-5.1
gMVP		0.38

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: rs183440070; hg19: chr14-31576376;