NM_004667.6:c.7594G>T

Variant names:

• chr15-28202136-C-A
• rs74005645
• NM_004667.6:c.7594G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004667.6(HERC2):​c.7594G>T​(p.Val2532Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2532M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017112643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.7594G>T	p.Val2532Leu	missense_variant	Exon 47 of 93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.7594G>T	p.Val2532Leu	missense_variant	Exon 47 of 93	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000567869.1	n.1704G>T		non_coding_transcript_exon_variant	Exon 2 of 10	2

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146576 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 178500 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000267 AC: 37 AN: 1383324 Hom.: 0 Cov.: 24 AF XY: 0.0000333 AC XY: 23 AN XY: 690878

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000108 AC: 3 AN: 27762

American (AMR) AF: 0.00 AC: 0 AN: 40492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 31132

South Asian (SAS) AF: 0.000314 AC: 26 AN: 82904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4804

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062298

Other (OTH) AF: 0.000141 AC: 8 AN: 56640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000136 AC: 2 AN: 146680 Hom.: 0 Cov.: 28 AF XY: 0.0000280 AC XY: 2 AN XY: 71412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000253 AC: 1 AN: 39518

American (AMR) AF: 0.00 AC: 0 AN: 14126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4084

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67512

Other (OTH) AF: 0.00 AC: 0 AN: 2034

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 38

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.046
DANN	Benign	0.37
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.11	N
PhyloP100		-0.17
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.027
Sift	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.15		Loss of sheet (P = 0.1907);
MVP		0.14
MPC		0.72
ClinPred		0.010	T
GERP RS		-4.4
Varity_R		0.017
gMVP		0.12
Mutation Taster		=100/0	polymorphism

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: rs74005645; hg19: chr15-28447282;