rs2228510

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18262 hom., cov: 30)

Exomes 𝑓: 0.51 ( 198800 hom. )

Consequence

HERC1
NM_003922.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.19

Publications

41 publications found

Variant links:

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]

HERC1 Gene-Disease associations (from GenCC):

macrocephaly, dysmorphic facies, and psychomotor retardation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
megalencephaly-severe kyphoscoliosis-overgrowth syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HERC1 links:

ENSG00000259589 (HGNC:):

ENSG00000259589 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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 rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.6658A>G	p.Ile2220Val	missense_variant	Exon 37 of 78	ENST00000443617.7	NP_003913.3	Q15751A0A024R5W0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7 link	c.6658A>G	p.Ile2220Val	missense_variant	Exon 37 of 78	1	NM_003922.4	ENSP00000390158.2		Q15751
ENSG00000259589	ENST00000559303.2 link	n.225T>C		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72618

AN:

151758

Hom.:

18247

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.444

AC:

110219

AN:

248302

AF XY:

0.446

show subpopulations

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 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.:

AF XY:

0.507

AC XY:

368434

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.451

AC:

15087

AN:

33472

American (AMR)

AF:

0.400

AC:

17847

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12797

AN:

26134

East Asian (EAS)

AF:

0.0632

AC:

2507

AN:

39674

South Asian (SAS)

AF:

0.350

AC:

30189

AN:

86236

European-Finnish (FIN)

AF:

0.406

AC:

21682

AN:

53348

Middle Eastern (MID)

AF:

0.458

AC:

2640

AN:

5768

European-Non Finnish (NFE)

AF:

0.554

AC:

615476

AN:

1111462

Other (OTH)

AF:

0.480

AC:

28957

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19313

38625

57938

77250

96563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16994

33988

50982

67976

84970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.479

AC:

72684

AN:

151876

Hom.:

18262

Cov.:

AF XY:

0.469

AC XY:

34815

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.457

AC:

18908

AN:

41372

American (AMR)

AF:

0.478

AC:

7304

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.483

AC:

1675

AN:

3470

East Asian (EAS)

AF:

0.0629

AC:

325

AN:

5168

South Asian (SAS)

AF:

0.327

AC:

1571

AN:

4810

European-Finnish (FIN)

AF:

0.399

AC:

4194

AN:

10520

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36904

AN:

67954

Other (OTH)

AF:

0.483

AC:

1020

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1805

3610

5416

7221

9026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.517

Hom.:

75404

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macrocephaly, dysmorphic facies, and psychomotor retardation

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.000081

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

PhyloP100

2.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.53

REVEL

Benign

0.059

Sift

Uncertain

0.0090

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.062

MPC

0.28

ClinPred

0.010

GERP RS

4.6

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.048

gMVP

0.30

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over