15-28120285-A-G

Variant names:

• chr15-28120285-A-G
• rs6497271
• NM_004667.6:c.13272+1061T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_004667.6(HERC2):​c.13272+1061T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.845 in 152,268 control chromosomes in the GnomAD database, including 58,036 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 0.85 (58036 hom., cov: 34)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.987 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	NM_004667.6	MANE Select	c.13272+1061T>C		intron	N/A	NP_004658.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.13272+1061T>C		intron	N/A	ENSP00000261609.8
	HERC2	ENST00000650509.1		n.*386+1061T>C		intron	N/A	ENSP00000496936.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128661 AN: 152150 Hom.: 58038 Cov.: 34

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.939

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.863

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.993

Gnomad OTH AF: 0.875

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

GnomAD4 genome AF: 0.845 AC: 128689 AN: 152268 Hom.: 58036 Cov.: 34 AF XY: 0.848 AC XY: 63189 AN XY: 74472

African (AFR) AF: 0.495 AC: 20530 AN: 41488

American (AMR) AF: 0.939 AC: 14380 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 3363 AN: 3472

East Asian (EAS) AF: 0.980 AC: 5077 AN: 5182

South Asian (SAS) AF: 0.863 AC: 4166 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10622

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.993 AC: 67563 AN: 68044

Other (OTH) AF: 0.869 AC: 1839 AN: 2116

Alfa AF: 0.904 Hom.: 18800

Bravo AF: 0.828

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		2.5
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: rs6497271; hg19: chr15-28365431;