15-28120472-A-G

Variant names:

• chr15-28120472-A-G
• rs12913832
• NM_004667.6:c.13272+874T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 334 publications found

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]

HERC2 Gene-Disease associations (from GenCC):

• developmental delay with autism spectrum disorder and gait instability

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004667.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	NM_004667.6	MANE Select	c.13272+874T>C		intron	N/A	NP_004658.3	O95714

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.13272+874T>C		intron	N/A	ENSP00000261609.8	O95714
	HERC2	ENST00000650509.1		n.*386+874T>C		intron	N/A	ENSP00000496936.1	A0A3B3IRP6

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

African (AFR) AF: 0.126 AC: 5236 AN: 41528

American (AMR) AF: 0.243 AC: 3715 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1986 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0910 AC: 439 AN: 4826

European-Finnish (FIN) AF: 0.885 AC: 9400 AN: 10616

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51909 AN: 67982

Other (OTH) AF: 0.346 AC: 730 AN: 2110

Alfa AF: 0.635 Hom.: 131866

Bravo AF: 0.423

Asia WGS AF: 0.0650 AC: 229 AN: 3478

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.68
PhyloP100		3.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12913832; hg19: chr15-28365618;