15-28228253-A-G

Position:

• chr15-28228253-A-G

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.5429T>C​(p.Met1810Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,613,724 control chromosomes in the GnomAD database, including 5 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 0.0024 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.131

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=0.016782314).
• BP6: Variant 15-28228253-A-G is Benign according to our data. Variant chr15-28228253-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28228253-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0024 (365/152330) while in subpopulation AFR AF= 0.00847 (352/41580). AF 95% confidence interval is 0.00774. There are 4 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.5429T>C	p.Met1810Thr	missense_variant	35/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.5429T>C	p.Met1810Thr	missense_variant	35/93	1	NM_004667.6	P1
HERC2	ENST00000569335.1	n.479T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152216 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00851

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000626 AC: 157 AN: 250990 Hom.: 1 AF XY: 0.000546 AC XY: 74 AN XY: 135650

Gnomad AFR exome AF: 0.00831

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000263 AC: 385 AN: 1461394 Hom.: 1 Cov.: 32 AF XY: 0.000239 AC XY: 174 AN XY: 727000

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152330 Hom.: 4 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74476

Gnomad4 AFR AF: 0.00847

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00269

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.016
DANN	Benign	0.18
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.64	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.032
Sift	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.32
MVP		0.10
MPC		0.84
ClinPred		0.0028	T
GERP RS		-3.4
Varity_R		0.038
gMVP		0.43

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: rs142072884; hg19: chr15-28473399;