rs147705404

chr15-28168546-G-Achr15-28168546-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004667.6(HERC2):c.10274C>T(p.Pro3425Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000742 in 1,614,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.79

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008213609).
• BP6: Variant 15-28168546-G-A is Benign according to our data. Variant chr15-28168546-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00361 (550/152330) while in subpopulation AFR AF= 0.0126 (522/41584). AF 95% confidence interval is 0.0117. There are 6 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.10274C>T	p.Pro3425Leu	missense_variant	67/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.10274C>T	p.Pro3425Leu	missense_variant	67/93	1	NM_004667.6	P1
HERC2	ENST00000569772.1	c.248C>T	p.Pro83Leu	missense_variant	3/5	5
HERC2	ENST00000650509.1	c.1985C>T	p.Pro662Leu	missense_variant, NMD_transcript_variant	15/39

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152212 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 250886 Hom.: 1 AF XY: 0.000745 AC XY: 101 AN XY: 135660

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000443 AC: 647 AN: 1461846 Hom.: 5 Cov.: 31 AF XY: 0.000384 AC XY: 279 AN XY: 727230

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152330 Hom.: 6 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74502

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000671 Hom.: 2

Bravo AF: 0.00439

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 23, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.27	T
Polyphen		0.015	B
Vest4		0.52
MVP		0.33
MPC		1.3
ClinPred		0.043	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.073
gMVP		0.41

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: rs147705404; hg19: chr15-28413692;