Genetic Variant HERC4:c.2337+333T>C (chr10-67954262-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015601.4(HERC4):c.2337+333T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 175,894 control chromosomes in the GnomAD database, including 1,167 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 971 hom., cov: 32)

Exomes 𝑓: 0.12 ( 196 hom. )

Consequence

HERC4
NM_015601.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.91

Publications

1 publications found

Variant links:

Genes affected

HERC4 (HGNC:24521): (HECT and RLD domain containing E3 ubiquitin protein ligase 4) HERC4 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).[supplied by OMIM, Mar 2008]

HERC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015601.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HERC4	NM_015601.4	MANE Select	c.2337+333T>C	intron	N/A	NP_056416.2
HERC4	NM_022079.3		c.2361+333T>C	intron	N/A	NP_071362.1
HERC4	NM_001278185.2		c.2361+333T>C	intron	N/A	NP_001265114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HERC4	ENST00000373700.9	TSL:1 MANE Select	c.2337+333T>C	intron	N/A	ENSP00000362804.4
HERC4	ENST00000395198.7	TSL:1	c.2361+333T>C	intron	N/A	ENSP00000378624.3
HERC4	ENST00000412272.6	TSL:1	c.2361+333T>C	intron	N/A	ENSP00000416504.2

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16849

AN:

152084

Hom.:

971

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0737

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.0995

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.118

GnomAD4 exome

AF:

0.119

AC:

2826

AN:

23692

Hom.:

196

Cov.:

AF XY:

0.119

AC XY:

1471

AN XY:

12330

show subpopulations

African (AFR)

AF:

0.0699

AC:

AN:

916

American (AMR)

AF:

0.136

AC:

122

AN:

898

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

112

AN:

984

East Asian (EAS)

AF:

0.120

AC:

182

AN:

1520

South Asian (SAS)

AF:

0.134

AC:

AN:

674

European-Finnish (FIN)

AF:

0.0833

AC:

AN:

816

Middle Eastern (MID)

AF:

0.0625

AC:

AN:

European-Non Finnish (NFE)

AF:

0.123

AC:

1986

AN:

16202

Other (OTH)

AF:

0.124

AC:

196

AN:

1586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

125

251

376

502

627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.111

AC:

16864

AN:

152202

Hom.:

971

Cov.:

AF XY:

0.111

AC XY:

8247

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0737

AC:

3063

AN:

41550

American (AMR)

AF:

0.140

AC:

2142

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

468

AN:

3470

East Asian (EAS)

AF:

0.130

AC:

676

AN:

5188

South Asian (SAS)

AF:

0.147

AC:

708

AN:

4822

European-Finnish (FIN)

AF:

0.0995

AC:

1054

AN:

10592

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.124

AC:

8430

AN:

67978

Other (OTH)

AF:

0.117

AC:

247

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

762

1524

2285

3047

3809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.115

Hom.:

171

Bravo

AF:

0.110

Asia WGS

AF:

0.127

AC:

442

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.7

(source)

DANN

Benign

0.78

PhyloP100

2.9

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over