Variant 10-67922971-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015601.4(HERC4):c.3110T>A(p.Ile1037Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000543 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

HERC4
NM_015601.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

Variant links:

Genes affected

HERC4 (HGNC:24521): (HECT and RLD domain containing E3 ubiquitin protein ligase 4) HERC4 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).[supplied by OMIM, Mar 2008]

HERC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0638378).

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC4	NM_015601.4 linkuse as main transcript	c.3110T>A	p.Ile1037Asn	missense_variant	25/25	ENST00000373700.9	NP_056416.2	Q5GLZ8-2A0A024QZN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC4	ENST00000373700.9 linkuse as main transcript	c.3110T>A	p.Ile1037Asn	missense_variant	25/25	1	NM_015601.4	ENSP00000362804.4		Q5GLZ8-2

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000391

AC:

AN:

250886

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000552

AC:

806

AN:

1461178

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

406

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000667

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000459

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000397

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

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

Dec 06, 2021

The c.3134T>A (p.I1045N) alteration is located in exon 26 (coding exon 24) of the HERC4 gene. This alteration results from a T to A substitution at nucleotide position 3134, causing the isoleucine (I) at amino acid position 1045 to be replaced by an asparagine (N). 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

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.28

.;.;T;.

Eigen

Benign

-0.083

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.064

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.25

.;.;N;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Benign

0.15

Sift

Benign

0.050

D;T;T;T

Sift4G

Benign

0.26

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.38

MVP

0.15

MPC

1.3

ClinPred

0.078

GERP RS

4.3

Varity_R

0.45

gMVP

0.76

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