Variant 14-31100976-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_015382.4(HECTD1):c.7787A>C(p.Glu2596Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HECTD1
NM_015382.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19

Variant links:

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]

HECTD1 links:

HECTD1 (HGNC:):

HECTD1 links:

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]

AP4S1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33824748).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD1	NM_015382.4 linkuse as main transcript	c.7787A>C	p.Glu2596Ala	missense_variant	43/43	ENST00000399332.6	NP_056197.3	Q9ULT8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD1	ENST00000399332.6 linkuse as main transcript	c.7787A>C	p.Glu2596Ala	missense_variant	43/43	5	NM_015382.4	ENSP00000382269.1		Q9ULT8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249396

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.7787A>C (p.E2596A) alteration is located in exon 43 (coding exon 42) of the HECTD1 gene. This alteration results from a A to C substitution at nucleotide position 7787, causing the glutamic acid (E) at amino acid position 2596 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

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;.;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.54

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.8

.;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0070

.;D;D

Sift4G

Uncertain

0.0090

D;D;D

Vest4

0.26

MutPred

0.58

.;Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);

MVP

0.50

MPC

1.4

ClinPred

0.93

GERP RS

4.4

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over