15-28114598-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004667.6(HERC2):c.13913+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.96 in 1,609,068 control chromosomes in the GnomAD database, including 751,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.85 (58175 hom., cov: 31)
  • Exomes 𝑓: 0.97 (693440 hom.)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.539

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-28114598-G-A is Benign according to our data. Variant chr15-28114598-G-A is described in ClinVar as [Benign]. Clinvar id is 1285341.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.13913+14C>T		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.13913+14C>T		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000566635.5	n.1038+14C>T		intron_variant, non_coding_transcript_variant		1
HERC2	ENST00000650509.1	c.*1027+14C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.849 AC: 128910 AN: 151902 Hom.: 58175 Cov.: 31

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.863

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.993

Gnomad OTH AF: 0.875

GnomAD3 exomes AF: 0.938 AC: 233938 AN: 249496 Hom.: 111720 AF XY: 0.942 AC XY: 127075 AN XY: 134906

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.970

Gnomad ASJ exome AF: 0.968

Gnomad EAS exome AF: 0.973

Gnomad SAS exome AF: 0.861

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.992

Gnomad OTH exome AF: 0.957

GnomAD4 exome AF: 0.972 AC: 1416156 AN: 1457048 Hom.: 693440 Cov.: 37 AF XY: 0.970 AC XY: 702478 AN XY: 724050

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.967

Gnomad4 ASJ exome AF: 0.968

Gnomad4 EAS exome AF: 0.979

Gnomad4 SAS exome AF: 0.866

Gnomad4 FIN exome AF: 0.999

Gnomad4 NFE exome AF: 0.995

Gnomad4 OTH exome AF: 0.946

GnomAD4 genome AF: 0.848 AC: 128941 AN: 152020 Hom.: 58175 Cov.: 31 AF XY: 0.852 AC XY: 63279 AN XY: 74310

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.941

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 0.978

Gnomad4 SAS AF: 0.862

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.993

Gnomad4 OTH AF: 0.869

Alfa AF: 0.942 Hom.: 18158

Bravo AF: 0.831

Asia WGS AF: 0.876 AC: 3045 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental delay with autism spectrum disorder and gait instability Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.1
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7495441; hg19: chr15-28359744;