Genetic Variant NM_015601.4:c.1011C>T (chr10-68014084-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_015601.4(HERC4):c.1011C>T(p.Ser337Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,611,320 control chromosomes in the GnomAD database, including 119,154 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 0.38 ( 12108 hom., cov: 31)

Exomes 𝑓: 0.37 ( 107046 hom. )

Consequence

HERC4
NM_015601.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Publications

25 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP7

Synonymous conserved (PhyloP=1.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC4	NM_015601.4 link	c.1011C>T	p.Ser337Ser	synonymous_variant	Exon 9 of 25	ENST00000373700.9	NP_056416.2	Q5GLZ8-2A0A024QZN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC4	ENST00000373700.9 link	c.1011C>T	p.Ser337Ser	synonymous_variant	Exon 9 of 25	1	NM_015601.4	ENSP00000362804.4		Q5GLZ8-2

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58410

AN:

151744

Hom.:

12089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.392

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.433

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.545

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.366

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.437

AC:

109631

AN:

250934

AF XY:

0.434

show subpopulations

Gnomad AFR exome

AF:

0.396

Gnomad AMR exome

AF:

0.567

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.853

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.368

AC:

536718

AN:

1459458

Hom.:

107046

Cov.:

AF XY:

0.372

AC XY:

269877

AN XY:

726168

show subpopulations

African (AFR)

AF:

0.384

AC:

12851

AN:

33438

American (AMR)

AF:

0.546

AC:

24346

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7955

AN:

26102

East Asian (EAS)

AF:

0.837

AC:

33218

AN:

39676

South Asian (SAS)

AF:

0.551

AC:

47405

AN:

86090

European-Finnish (FIN)

AF:

0.403

AC:

21520

AN:

53394

Middle Eastern (MID)

AF:

0.400

AC:

2309

AN:

5768

European-Non Finnish (NFE)

AF:

0.328

AC:

364521

AN:

1110094

Other (OTH)

AF:

0.375

AC:

22593

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

15989

31979

47968

63958

79947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12252

24504

36756

49008

61260

<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:

0.385

AC:

58466

AN:

151862

Hom.:

12108

Cov.:

AF XY:

0.393

AC XY:

29175

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.392

AC:

16196

AN:

41344

American (AMR)

AF:

0.434

AC:

6632

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1096

AN:

3468

East Asian (EAS)

AF:

0.848

AC:

4378

AN:

5164

South Asian (SAS)

AF:

0.545

AC:

2624

AN:

4812

European-Finnish (FIN)

AF:

0.409

AC:

4310

AN:

10548

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.322

AC:

21884

AN:

67950

Other (OTH)

AF:

0.384

AC:

808

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1756

3512

5268

7024

8780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

564

1128

1692

2256

2820

<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:

0.335

Hom.:

14836

Bravo

AF:

0.391

Asia WGS

AF:

0.613

AC:

2129

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.308

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.3

(source)

DANN

Benign

0.72

PhyloP100

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=91/9

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

Computational scores

Splicing

Publications

Other links and lift over