rs1667394

Variant names:

• chr15-28285036-C-T
• rs1667394
• NM_004667.6:c.323-4749G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-28285036-C-T
• chr15-28285036-C-A
• chr15-28285036-C-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.323-4749G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 150,464 control chromosomes in the GnomAD database, including 33,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.60 (33986 hom., cov: 29)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.540
• Publications: 70 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 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.323-4749G>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.323-4749G>A		intron	N/A	ENSP00000261609.8	O95714
	HERC2	ENST00000564734.5	TSL:1	n.*193-4749G>A		intron	N/A	ENSP00000456237.1	H3BRG9
	HERC2	ENST00000564383.1	TSL:3	n.218-4749G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.603 AC: 90649 AN: 150360 Hom.: 33988 Cov.: 29

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.967

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.602 AC: 90643 AN: 150464 Hom.: 33986 Cov.: 29 AF XY: 0.598 AC XY: 43968 AN XY: 73516

African (AFR) AF: 0.188 AC: 7605 AN: 40508

American (AMR) AF: 0.559 AC: 8447 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2543 AN: 3466

East Asian (EAS) AF: 0.255 AC: 1281 AN: 5014

South Asian (SAS) AF: 0.375 AC: 1783 AN: 4752

European-Finnish (FIN) AF: 0.967 AC: 10096 AN: 10444

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57004 AN: 67882

Other (OTH) AF: 0.552 AC: 1153 AN: 2090

Alfa AF: 0.739 Hom.: 197105

Bravo AF: 0.552

Asia WGS AF: 0.335 AC: 1166 AN: 3478

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.43
PhyloP100		-0.54
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: rs1667394; hg19: chr15-28530182;