rs2228510

Positions:

• chr15-63678257-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003922.4(HERC1):​c.6658A>G​(p.Ile2220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,612,970 control chromosomes in the GnomAD database, including 217,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18262 hom., cov: 30)
  • Exomes 𝑓: 0.51 (198800 hom.)
• Consequence: HERC1 NM_003922.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.19

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]

ENSG00000259589 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HERC1. . Gene score misZ 4.9558 (greater than the threshold 3.09). Trascript score misZ 5.2706 (greater than threshold 3.09). GenCC has associacion of gene with macrocephaly, dysmorphic facies, and psychomotor retardation, megalencephaly-severe kyphoscoliosis-overgrowth syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=8.076119E-5).
• BP6: Variant 15-63678257-T-C is Benign according to our data. Variant chr15-63678257-T-C is described in ClinVar as [Benign]. Clinvar id is 1260045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC1	NM_003922.4	c.6658A>G	p.Ile2220Val	missense_variant	37/78	ENST00000443617.7	NP_003913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7	c.6658A>G	p.Ile2220Val	missense_variant	37/78	1	NM_003922.4	ENSP00000390158.2
ENSG00000259589	ENST00000559303.2	n.225T>C		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72618 AN: 151758 Hom.: 18247 Cov.: 30

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.481

GnomAD3 exomes AF: 0.444 AC: 110219 AN: 248302 Hom.: 26880 AF XY: 0.446 AC XY: 60020 AN XY: 134718

Gnomad AFR exome AF: 0.452

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.0574

Gnomad SAS exome AF: 0.351

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.549

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.511 AC: 747182 AN: 1461094 Hom.: 198800 Cov.: 45 AF XY: 0.507 AC XY: 368434 AN XY: 726796

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.0632

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.480

GnomAD4 genome AF: 0.479 AC: 72684 AN: 151876 Hom.: 18262 Cov.: 30 AF XY: 0.469 AC XY: 34815 AN XY: 74222

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.483

Alfa AF: 0.524 Hom.: 54364

Bravo AF: 0.481

TwinsUK AF: 0.564 AC: 2093

ALSPAC AF: 0.566 AC: 2180

ESP6500AA AF: 0.471 AC: 1817

ESP6500EA AF: 0.548 AC: 4546

ExAC AF: 0.446 AC: 53876

Asia WGS AF: 0.238 AC: 828 AN: 3478

EpiCase AF: 0.537

EpiControl AF: 0.543

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Macrocephaly, dysmorphic facies, and psychomotor retardation 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.000081	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.059
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.062
MPC		0.28
ClinPred		0.010	T
GERP RS		4.6
Varity_R		0.048
gMVP		0.30

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: rs2228510; hg19: chr15-63970456; COSMIC: COSV71246773; COSMIC: COSV71246773;