rs8039195

chr15-28270938-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):c.1084-70G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,370,128 control chromosomes in the GnomAD database, including 438,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.65 (37311 hom., cov: 33)
  • Exomes 𝑓: 0.79 (401532 hom.)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.302

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.1084-70G>A		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.1084-70G>A		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000564734.5	c.*954-70G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98690 AN: 151986 Hom.: 37319 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.621

GnomAD4 exome AF: 0.792 AC: 964831 AN: 1218024 Hom.: 401532 AF XY: 0.782 AC XY: 477529 AN XY: 610762

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.772

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.967

Gnomad4 NFE exome AF: 0.862

Gnomad4 OTH exome AF: 0.728

GnomAD4 genome AF: 0.649 AC: 98686 AN: 152104 Hom.: 37311 Cov.: 33 AF XY: 0.644 AC XY: 47898 AN XY: 74380

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.763

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.969

Gnomad4 NFE AF: 0.862

Gnomad4 OTH AF: 0.617

Alfa AF: 0.771 Hom.: 27517

Bravo AF: 0.609

Asia WGS AF: 0.389 AC: 1353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.5
Dann	Benign	0.38

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: rs8039195; hg19: chr15-28516084;