rs145370046

Positions:

• chr15-28211013-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004667.6(HERC2):​c.7058C>G​(p.Thr2353Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00629 in 151,430 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.62

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 -19 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=0.0038871765).
• BP6: Variant 15-28211013-G-C is Benign according to our data. Variant chr15-28211013-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 376985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28211013-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00629 (953/151430) while in subpopulation AFR AF= 0.0131 (540/41166). AF 95% confidence interval is 0.0122. There are 6 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.7058C>G	p.Thr2353Ser	missense_variant	44/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.7058C>G	p.Thr2353Ser	missense_variant	44/93	1	NM_004667.6	P1

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 951 AN: 151322 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00227

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00155 AC: 385 AN: 247628 Hom.: 6 AF XY: 0.00152 AC XY: 204 AN XY: 134342

Gnomad AFR exome AF: 0.00746

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000826

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00148 AC: 2113 AN: 1423402 Hom.: 10 Cov.: 27 AF XY: 0.00148 AC XY: 1054 AN XY: 710048

Gnomad4 AFR exome AF: 0.00857

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.000606

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.000816

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00629 AC: 953 AN: 151430 Hom.: 6 Cov.: 30 AF XY: 0.00689 AC XY: 510 AN XY: 73984

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00315

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00227

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00352 Hom.: 1

ExAC AF: 0.00363 AC: 437

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	HERC2: BP4, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.18
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.17		Loss of glycosylation at T2353 (P = 0.0182);
MVP		0.23
MPC		0.65
ClinPred		0.0098	T
GERP RS		2.5
Varity_R		0.036
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs145370046; hg19: chr15-28456159; COSMIC: COSV55318251;