rs2229749

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.11166G>C(p.Glu3722Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 1,611,522 control chromosomes in the GnomAD database, including 569,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E3722E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.81 ( 52232 hom., cov: 31)

Exomes 𝑓: 0.83 ( 516876 hom. )

Consequence

HERC1
NM_003922.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.198

Publications

32 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:

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=6.446062E-7).

BP6

Variant 15-63645010-C-G is Benign according to our data. Variant chr15-63645010-C-G is described in ClinVar as Benign. ClinVar VariationId is 1243466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.11166G>C	p.Glu3722Asp	missense_variant	Exon 57 of 78	ENST00000443617.7	NP_003913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC1	ENST00000443617.7 link	c.11166G>C	p.Glu3722Asp	missense_variant	Exon 57 of 78	1	NM_003922.4	ENSP00000390158.2

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123679

AN:

151980

Hom.:

52185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.852

Gnomad AMI

AF:

0.887

Gnomad AMR

AF:

0.724

Gnomad ASJ

AF:

0.859

Gnomad EAS

AF:

0.0958

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.825

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.876

Gnomad OTH

AF:

0.806

GnomAD2 exomes

AF:

0.739

AC:

184014

AN:

249060

AF XY:

0.745

show subpopulations

Gnomad AFR exome

AF:

0.851

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.862

Gnomad EAS exome

AF:

0.0824

Gnomad FIN exome

AF:

0.829

Gnomad NFE exome

AF:

0.879

Gnomad OTH exome

AF:

0.803

GnomAD4 exome

AF:

0.828

AC:

1208137

AN:

1459424

Hom.:

516876

Cov.:

AF XY:

0.824

AC XY:

598206

AN XY:

726170

show subpopulations

African (AFR)

AF:

0.852

AC:

28492

AN:

33434

American (AMR)

AF:

0.577

AC:

25801

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.861

AC:

22479

AN:

26112

East Asian (EAS)

AF:

0.0843

AC:

3343

AN:

39658

South Asian (SAS)

AF:

0.643

AC:

55428

AN:

86186

European-Finnish (FIN)

AF:

0.834

AC:

44511

AN:

53386

Middle Eastern (MID)

AF:

0.833

AC:

4801

AN:

5766

European-Non Finnish (NFE)

AF:

0.879

AC:

975053

AN:

1109900

Other (OTH)

AF:

0.800

AC:

48229

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7958

15916

23874

31832

39790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20938

41876

62814

83752

104690

<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:

0.814

AC:

123782

AN:

152098

Hom.:

52232

Cov.:

AF XY:

0.802

AC XY:

59596

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.852

AC:

35332

AN:

41476

American (AMR)

AF:

0.723

AC:

11040

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.859

AC:

2982

AN:

3472

East Asian (EAS)

AF:

0.0957

AC:

495

AN:

5174

South Asian (SAS)

AF:

0.603

AC:

2903

AN:

4818

European-Finnish (FIN)

AF:

0.825

AC:

8719

AN:

10568

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.876

AC:

59545

AN:

68004

Other (OTH)

AF:

0.807

AC:

1705

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

996

1992

2987

3983

4979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.834

Hom.:

29651

Bravo

AF:

0.803

TwinsUK

AF:

0.876

AC:

3248

ALSPAC

AF:

0.873

AC:

3365

ESP6500AA

AF:

0.857

AC:

3337

ESP6500EA

AF:

0.880

AC:

7302

ExAC

AF:

0.747

AC:

90265

Asia WGS

AF:

0.404

AC:

1406

AN:

3478

EpiCase

AF:

0.877

EpiControl

AF:

0.880

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.072

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.11

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.44

MetaRNN

Benign

6.4e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.55

PhyloP100

-0.20

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.050

REVEL

Benign

0.049

Sift

Benign

0.72

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.0090

MutPred

0.19

Loss of disorder (P = 0.1792);

MPC

0.30

ClinPred

0.0014

GERP RS

-3.3

Varity_R

0.038

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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