chr10-67925118-C-T

Variant summary

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

The NM_015601.4(HERC4):​c.2908G>A​(p.Glu970Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,601,320 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 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HERC4
NM_015601.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69
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]

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=0.2792758).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HERC4NM_015601.4 linkc.2908G>A p.Glu970Lys missense_variant Exon 24 of 25 ENST00000373700.9 NP_056416.2 Q5GLZ8-2A0A024QZN8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HERC4ENST00000373700.9 linkc.2908G>A p.Glu970Lys missense_variant Exon 24 of 25 1 NM_015601.4 ENSP00000362804.4 Q5GLZ8-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250790
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135588
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000617
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000139
AC:
201
AN:
1449172
Hom.:
0
Cov.:
27
AF XY:
0.000139
AC XY:
100
AN XY:
721786
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000177
Gnomad4 OTH exome
AF:
0.0000834
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000128
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2932G>A (p.E978K) alteration is located in exon 25 (coding exon 23) of the HERC4 gene. This alteration results from a G to A substitution at nucleotide position 2932, causing the glutamic acid (E) at amino acid position 978 to be replaced by a lysine (K). 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
0.16
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;.;T;.
Eigen
Benign
0.055
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
.;.;L;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.0
D;D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.014
D;D;D;D
Sift4G
Benign
0.11
T;T;T;T
Polyphen
0.24
B;B;B;B
Vest4
0.40
MutPred
0.64
.;.;Gain of methylation at E978 (P = 0.0017);.;
MVP
0.44
MPC
1.0
ClinPred
0.51
D
GERP RS
5.7
Varity_R
0.22
gMVP
0.67

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.

Other links and lift over

dbSNP: rs758125569; hg19: chr10-69684875; COSMIC: COSV99517461; API