15-28270938-C-T

Variant names:

• chr15-28270938-C-T
• rs8039195
• NM_004667.6:c.1084-70G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 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 -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.

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.1084-70G>A		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.1084-70G>A		intron	N/A	ENSP00000261609.8	O95714
	HERC2	ENST00000564734.5	TSL:1	n.*954-70G>A		intron	N/A	ENSP00000456237.1	H3BRG9

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

African (AFR) AF: 0.277 AC: 7810 AN: 28174

American (AMR) AF: 0.597 AC: 21066 AN: 35290

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 18051 AN: 23370

East Asian (EAS) AF: 0.255 AC: 9167 AN: 36016

South Asian (SAS) AF: 0.432 AC: 32203 AN: 74564

European-Finnish (FIN) AF: 0.967 AC: 48354 AN: 49990

Middle Eastern (MID) AF: 0.572 AC: 2106 AN: 3680

European-Non Finnish (NFE) AF: 0.862 AC: 788169 AN: 914852

Other (OTH) AF: 0.728 AC: 37905 AN: 52088

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

African (AFR) AF: 0.298 AC: 12332 AN: 41448

American (AMR) AF: 0.610 AC: 9319 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2647 AN: 3470

East Asian (EAS) AF: 0.266 AC: 1370 AN: 5158

South Asian (SAS) AF: 0.427 AC: 2056 AN: 4810

European-Finnish (FIN) AF: 0.969 AC: 10294 AN: 10622

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.862 AC: 58583 AN: 67998

Other (OTH) AF: 0.617 AC: 1304 AN: 2112

Alfa AF: 0.766 Hom.: 31621

Bravo AF: 0.609

Asia WGS AF: 0.389 AC: 1353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.5
DANN	Benign	0.38
PhyloP100		0.30
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: rs8039195; hg19: chr15-28516084;