rs143508709

chr15-63645525-C-T

Variant summary

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

The NM_003922.4(HERC1):c.11036G>A(p.Arg3679His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,611,716 control chromosomes in the GnomAD database, including 9 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 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: HERC1 NM_003922.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.317

Genes affected

HERC1 (HGNC:4867): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1) This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008111596).
• BP6: Variant 15-63645525-C-T is Benign according to our data. Variant chr15-63645525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63645525-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152258) while in subpopulation AFR AF= 0.0184 (763/41550). AF 95% confidence interval is 0.0173. There are 4 homozygotes in gnomad4. There are 354 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC1	NM_003922.4	c.11036G>A	p.Arg3679His	missense_variant	56/78	ENST00000443617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC1	ENST00000443617.7	c.11036G>A	p.Arg3679His	missense_variant	56/78	1	NM_003922.4	P1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 794 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00133 AC: 327 AN: 246124 Hom.: 2 AF XY: 0.000921 AC XY: 123 AN XY: 133546

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000973

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000837

GnomAD4 exome AF: 0.000524 AC: 765 AN: 1459458 Hom.: 5 Cov.: 31 AF XY: 0.000441 AC XY: 320 AN XY: 725976

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00521 AC: 793 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00475 AC XY: 354 AN XY: 74454

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.000865 Hom.: 1

Bravo AF: 0.00596

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0146 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 25363768) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 17, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.071	T
Polyphen		0.0	B
Vest4		0.085
MVP		0.043
MPC		0.41
ClinPred		0.020	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.034
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143508709; hg19: chr15-63937724; COSMIC: COSV101496343;