rs80203202

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003922.4(HERC1):c.3374G>A(p.Gly1125Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,613,808 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 6 hom. )

Consequence

HERC1
NM_003922.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 7.24

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019063026).

BP6

Variant 15-63725486-C-T is Benign according to our data. Variant chr15-63725486-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377238.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (321/152164) while in subpopulation NFE AF = 0.00328 (223/68008). AF 95% confidence interval is 0.00293. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.3374G>A	p.Gly1125Asp	missense_variant	Exon 18 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.3374G>A	p.Gly1125Asp	missense_variant	Exon 18 of 78	1	NM_003922.4	ENSP00000390158.2		Q15751
HERC1	ENST00000561400.1 link	c.931-9013G>A		intron_variant	Intron 2 of 7	2		ENSP00000453937.1		H0YNB1

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

321

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00328

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00205

AC:

510

AN:

248816

AF XY:

0.00202

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00677

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.00285

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00298

AC:

4356

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2069

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.00203

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00700

AC:

183

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000777

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00340

AC:

3784

AN:

1111810

Other (OTH)

AF:

0.00242

AC:

146

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

207

414

620

827

1034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.00211

AC:

321

AN:

152164

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41510

American (AMR)

AF:

0.00183

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00328

AC:

223

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00278

Hom.:

Bravo

AF:

0.00218

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000510

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00210

AC:

254

EpiCase

AF:

0.00344

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HERC1: BS1 -

Oct 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jul 20, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HERC1 c.3374G>A (p.Gly1125Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 248816 control chromosomes (gnomAD). c.3374G>A has been reported in the literature in individuals affected with schizophrenia (Mojarad_2021). These reports do not provide unequivocal conclusions about association of the variant with Macrocephaly, Dysmorphic Facies, And Psychomotor Retardation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Macrocephaly, dysmorphic facies, and psychomotor retardation

Uncertain:1

Sep 12, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 14, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HERC1-related disorder

Benign:1

Feb 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0052

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

7.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.010

REVEL

Benign

0.18

Sift

Benign

0.23

Sift4G

Benign

0.39

Polyphen

0.99

Vest4

0.85

MVP

0.15

MPC

0.43

ClinPred

0.033

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.62

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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