rs145594989

chr15-28234279-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_004667.6(HERC2):c.4009C>T(p.Leu1337Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00095 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.66

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074782073).
• BP6: Variant 15-28234279-G-A is Benign according to our data. Variant chr15-28234279-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377360.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-28234279-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.4009C>T	p.Leu1337Phe	missense_variant	27/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.4009C>T	p.Leu1337Phe	missense_variant	27/93	1	NM_004667.6	P1

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1395 AN: 151512 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00612

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00239 AC: 594 AN: 248402 Hom.: 0 AF XY: 0.00188 AC XY: 254 AN XY: 134916

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000990

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000945 AC: 1372 AN: 1451642 Hom.: 0 Cov.: 28 AF XY: 0.000808 AC XY: 584 AN XY: 722780

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000625

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00925 AC: 1402 AN: 151628 Hom.: 0 Cov.: 22 AF XY: 0.00854 AC XY: 633 AN XY: 74128

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00611

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00552 Hom.: 0

ESP6500AA AF: 0.0280 AC: 123

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00311 AC: 372

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

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.092
Sift	Benign	0.082	T
Polyphen		0.97	D
Vest4		0.63
MVP		0.40
MPC		1.8
ClinPred		0.037	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145594989; hg19: chr15-28479425; COSMIC: COSV99079412; COSMIC: COSV99079412;