15-28195141-T-C

Variant names:

• chr15-28195141-T-C
• rs6497287
• NM_004667.6:c.8260+1074A>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.8260+1074A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,196 control chromosomes in the GnomAD database, including 1,198 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 0.11 (1198 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207
• Publications: 24 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.8260+1074A>G		intron_variant	Intron 52 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.8260+1074A>G		intron_variant	Intron 52 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000567869.1	n.2370+1074A>G		intron_variant	Intron 7 of 9	2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16120 AN: 152078 Hom.: 1192 Cov.: 32

Gnomad AFR AF: 0.0977

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.106 AC: 16134 AN: 152196 Hom.: 1198 Cov.: 32 AF XY: 0.109 AC XY: 8134 AN XY: 74418

African (AFR) AF: 0.0975 AC: 4049 AN: 41524

American (AMR) AF: 0.229 AC: 3503 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3466

East Asian (EAS) AF: 0.294 AC: 1522 AN: 5178

South Asian (SAS) AF: 0.199 AC: 960 AN: 4824

European-Finnish (FIN) AF: 0.0195 AC: 206 AN: 10588

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0752 AC: 5112 AN: 68008

Other (OTH) AF: 0.133 AC: 281 AN: 2116

Alfa AF: 0.0955 Hom.: 1908

Bravo AF: 0.121

Asia WGS AF: 0.210 AC: 729 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.89
PhyloP100		0.21
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: rs6497287; hg19: chr15-28440287;