chr15-28111713-C-T

Variant names:

• chr15-28111713-C-T
• rs1129038
• NM_004667.6:c.*50G>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.*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
• Publications: 115 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.756 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.*50G>A		3_prime_UTR	Exon 93 of 93	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.*50G>A		3_prime_UTR	Exon 93 of 93	ENSP00000261609.8	O95714
	HERC2	ENST00000566635.5	TSL:1	n.1680G>A		non_coding_transcript_exon	Exon 7 of 7
	HERC2	ENST00000650509.1		n.*1669G>A		non_coding_transcript_exon	Exon 39 of 39	ENSP00000496936.1	A0A3B3IRP6

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

GnomAD2 exomes AF: 0.493 AC: 119373 AN: 242098 AF XY: 0.493

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 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

African (AFR) AF: 0.0996 AC: 3289 AN: 33028

American (AMR) AF: 0.178 AC: 7796 AN: 43896

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 14690 AN: 25034

East Asian (EAS) AF: 0.000684 AC: 27 AN: 39450

South Asian (SAS) AF: 0.102 AC: 8474 AN: 83484

European-Finnish (FIN) AF: 0.877 AC: 46360 AN: 52880

Middle Eastern (MID) AF: 0.189 AC: 1035 AN: 5490

European-Non Finnish (NFE) AF: 0.770 AC: 844731 AN: 1096888

Other (OTH) AF: 0.567 AC: 33690 AN: 59396

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

African (AFR) AF: 0.126 AC: 5233 AN: 41520

American (AMR) AF: 0.244 AC: 3722 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1983 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5172

South Asian (SAS) AF: 0.0905 AC: 436 AN: 4816

European-Finnish (FIN) AF: 0.874 AC: 9270 AN: 10610

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51796 AN: 67986

Other (OTH) AF: 0.347 AC: 732 AN: 2112

Alfa AF: 0.624 Hom.: 102639

Bravo AF: 0.422

Asia WGS AF: 0.0650 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.16
DANN	Benign	0.78
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1129038; hg19: chr15-28356859;