15-28128866-T-C

Variant names:

• chr15-28128866-T-C
• rs3935591
• NM_004667.6:c.12802+1297A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):​c.12802+1297A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,066 control chromosomes in the GnomAD database, including 37,510 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 (37510 hom., cov: 31)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 16 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• 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 rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.12802+1297A>G		intron_variant	Intron 83 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.12802+1297A>G		intron_variant	Intron 83 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000650509.1	n.4281+3234A>G		intron_variant	Intron 29 of 38			ENSP00000496936.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99409 AN: 151948 Hom.: 37516 Cov.: 31

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.621

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

GnomAD4 genome AF: 0.654 AC: 99409 AN: 152066 Hom.: 37510 Cov.: 31 AF XY: 0.649 AC XY: 48260 AN XY: 74360

African (AFR) AF: 0.316 AC: 13116 AN: 41462

American (AMR) AF: 0.612 AC: 9339 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2582 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1369 AN: 5140

South Asian (SAS) AF: 0.430 AC: 2068 AN: 4806

European-Finnish (FIN) AF: 0.968 AC: 10285 AN: 10620

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.862 AC: 58566 AN: 67980

Other (OTH) AF: 0.618 AC: 1307 AN: 2114

Alfa AF: 0.756 Hom.: 64533

Bravo AF: 0.615

Asia WGS AF: 0.382 AC: 1331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.2
DANN	Benign	0.84
PhyloP100		0.20
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: rs3935591; hg19: chr15-28374012;