rs1129038

chr15-28111713-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):c.*50G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,591,722 control chromosomes in the GnomAD database, including 392,098 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 0.49 (25922 hom., cov: 33)
  • Exomes 𝑓: 0.67 (366176 hom.)
• Consequence: HERC2 NM_004667.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.*50G>A		3_prime_UTR_variant	93/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.*50G>A		3_prime_UTR_variant	93/93	1	NM_004667.6	P1
HERC2	ENST00000566635.5	n.1680G>A		non_coding_transcript_exon_variant	7/7	1
HERC2	ENST00000650509.1	c.*1669G>A		3_prime_UTR_variant, NMD_transcript_variant	39/39
HERC2	ENST00000562136.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73830 AN: 152058 Hom.: 25928 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.350

GnomAD3 exomes AF: 0.493 AC: 119373 AN: 242098 Hom.: 43542 AF XY: 0.493 AC XY: 64197 AN XY: 130228

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.000818

Gnomad SAS exome AF: 0.0971

Gnomad FIN exome AF: 0.876

Gnomad NFE exome AF: 0.751

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.667 AC: 960092 AN: 1439546 Hom.: 366176 Cov.: 28 AF XY: 0.651 AC XY: 464607 AN XY: 713946

Gnomad4 AFR exome AF: 0.0996

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.587

Gnomad4 EAS exome AF: 0.000684

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.877

Gnomad4 NFE exome AF: 0.770

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.485 AC: 73814 AN: 152176 Hom.: 25922 Cov.: 33 AF XY: 0.472 AC XY: 35135 AN XY: 74408

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0905

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.762

Gnomad4 OTH AF: 0.347

Alfa AF: 0.628 Hom.: 35998

Bravo AF: 0.422

Asia WGS AF: 0.0650 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.16
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1129038; hg19: chr15-28356859;