rs139953376

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004667.6(HERC2):​c.10969G>A​(p.Val3657Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,064 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0035 ( 11 hom. )

Consequence

HERC2
NM_004667.6 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.779
Variant links:
Genes affected
HERC2 (HGNC:4868): (HECT and RLD domain containing E3 ubiquitin protein ligase 2) This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0058249235).
BP6
Variant 15-28146276-C-T is Benign according to our data. Variant chr15-28146276-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28146276-C-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HERC2NM_004667.6 linkc.10969G>A p.Val3657Ile missense_variant Exon 71 of 93 ENST00000261609.13 NP_004658.3 O95714A8KAQ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HERC2ENST00000261609.13 linkc.10969G>A p.Val3657Ile missense_variant Exon 71 of 93 1 NM_004667.6 ENSP00000261609.8 O95714
HERC2ENST00000650509.1 linkn.2680G>A non_coding_transcript_exon_variant Exon 19 of 39 ENSP00000496936.1 A0A3B3IRP6

Frequencies

GnomAD3 genomes
AF:
0.00254
AC:
387
AN:
152078
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000869
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00575
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00397
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00282
AC:
710
AN:
251430
Hom.:
3
AF XY:
0.00274
AC XY:
373
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000555
Gnomad FIN exome
AF:
0.00905
Gnomad NFE exome
AF:
0.00380
Gnomad OTH exome
AF:
0.00408
GnomAD4 exome
AF:
0.00346
AC:
5054
AN:
1461868
Hom.:
11
Cov.:
31
AF XY:
0.00343
AC XY:
2493
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.000402
Gnomad4 ASJ exome
AF:
0.00184
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000499
Gnomad4 FIN exome
AF:
0.00876
Gnomad4 NFE exome
AF:
0.00386
Gnomad4 OTH exome
AF:
0.00281
GnomAD4 genome
AF:
0.00254
AC:
387
AN:
152196
Hom.:
0
Cov.:
31
AF XY:
0.00232
AC XY:
173
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.000867
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000416
Gnomad4 FIN
AF:
0.00575
Gnomad4 NFE
AF:
0.00397
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00346
Hom.:
2
Bravo
AF:
0.00199
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00389
AC:
15
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00314
AC:
27
ExAC
AF:
0.00247
AC:
300
EpiCase
AF:
0.00229
EpiControl
AF:
0.00338

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2025HERC2: BP4, BS2 -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 19, 2017- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2022This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
HERC2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 30, 2024This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
9.1
DANN
Benign
0.57
DEOGEN2
Benign
0.091
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.0058
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-2.1
N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.74
N
REVEL
Benign
0.042
Sift
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.15
MVP
0.093
MPC
0.59
ClinPred
0.0016
T
GERP RS
1.9
Varity_R
0.012
gMVP
0.26

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: rs139953376; hg19: chr15-28391422; API