NM_004667.6:c.323-4749G>A

Variant names:

• chr15-28285036-C-T
• rs1667394
• NM_004667.6:c.323-4749G>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.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: 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.323-4749G>A		intron_variant	Intron 4 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.323-4749G>A		intron_variant	Intron 4 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000564734.5	n.*193-4749G>A		intron_variant	Intron 5 of 20	1		ENSP00000456237.1
HERC2	ENST00000564383.1	n.218-4749G>A		intron_variant	Intron 2 of 2	3

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

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Other:1

Feb 13, 2018

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;