15-28120472-A-G

Position:

• chr15-28120472-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004667.6(HERC2):​c.13272+874T>C variant causes a intron change. The variant allele was found at a frequency of 0.487 in 152,216 control chromosomes in the GnomAD database, including 26,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.49 (26125 hom., cov: 33)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 3.94

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.13272+874T>C		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.13272+874T>C		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000650509.1	c.*386+874T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74071 AN: 152098 Hom.: 26131 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.350

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.487 AC: 74054 AN: 152216 Hom.: 26125 Cov.: 33 AF XY: 0.474 AC XY: 35273 AN XY: 74416

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0910

Gnomad4 FIN AF: 0.885

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.346

Alfa AF: 0.633 Hom.: 56047

Bravo AF: 0.423

Asia WGS AF: 0.0650 AC: 229 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Other:1

association, no assertion criteria provided

literature only

OMIM

Feb 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.68

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: rs12913832; hg19: chr15-28365618;