15-28113673-T-C

Position:

• chr15-28113673-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_004667.6(HERC2):​c.13919A>G​(p.His4640Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,613,752 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (28 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.24

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 -9 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HERC2. . Gene score misZ 4.4237 (greater than the threshold 3.09). Trascript score misZ 7.8111 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay with autism spectrum disorder and gait instability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014858425).
• BP6: Variant 15-28113673-T-C is Benign according to our data. Variant chr15-28113673-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2498604.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-28113673-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.13919A>G	p.His4640Arg	missense_variant	91/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.13919A>G	p.His4640Arg	missense_variant	91/93	1	NM_004667.6	P1
HERC2	ENST00000566635.5	n.1044A>G		non_coding_transcript_exon_variant	5/7	1
HERC2	ENST00000562136.1	n.45A>G		non_coding_transcript_exon_variant	1/3	2
HERC2	ENST00000650509.1	c.*1033A>G		3_prime_UTR_variant, NMD_transcript_variant	37/39

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00339 AC: 851 AN: 251050 Hom.: 9 AF XY: 0.00333 AC XY: 452 AN XY: 135710

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00224 AC: 3281 AN: 1461474 Hom.: 28 Cov.: 31 AF XY: 0.00235 AC XY: 1707 AN XY: 727096

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74466

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00523

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00358 Hom.: 14

Bravo AF: 0.00175

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00354 AC: 430

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

HERC2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.82
MPC		1.3
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.67
gMVP		0.66

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: rs138725743; hg19: chr15-28358819;