dbSNP rs7182782: HERC1:p.Gly3517Arg (chr15-63649923-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003922.4(HERC1):c.10549G>A(p.Gly3517Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HERC1
NM_003922.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.68

Publications

2 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC1	NM_003922.4 link	c.10549G>A	p.Gly3517Arg	missense_variant, splice_region_variant	Exon 54 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.10549G>A	p.Gly3517Arg	missense_variant, splice_region_variant	Exon 54 of 78	1	NM_003922.4	ENSP00000390158.2		Q15751

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715096

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33020

American (AMR)

AF:

0.00

AC:

AN:

41652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25602

East Asian (EAS)

AF:

0.00

AC:

AN:

39010

South Asian (SAS)

AF:

0.00

AC:

AN:

82782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101058

Other (OTH)

AF:

0.00

AC:

AN:

59710

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.3

PhyloP100

7.7

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.43

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.91

MutPred

0.31

Gain of MoRF binding (P = 0.0071);

MVP

0.37

MPC

1.2

ClinPred

0.98

GERP RS

5.9

Varity_R

0.29

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over