Variant 4-88398144-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017912.4(HERC6):c.1027T>C(p.Phe343Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,578,912 control chromosomes in the GnomAD database, including 64,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.37 ( 15581 hom., cov: 32)

Exomes 𝑓: 0.21 ( 48884 hom. )

Consequence

HERC6
NM_017912.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.330

Variant links:

Genes affected

HERC6 (HGNC:26072): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 6) HERC6 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]

HERC6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0141398E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC6	NM_017912.4 linkuse as main transcript	c.1027T>C	p.Phe343Leu	missense_variant, splice_region_variant	8/23	ENST00000264346.12	NP_060382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC6	ENST00000264346.12 linkuse as main transcript	c.1027T>C	p.Phe343Leu	missense_variant, splice_region_variant	8/23	1	NM_017912.4	ENSP00000264346	P1	Q8IVU3-1
HERC6	ENST00000380265.9 linkuse as main transcript	c.1027T>C	p.Phe343Leu	missense_variant, splice_region_variant	8/22	1		ENSP00000369617		Q8IVU3-2
HERC6	ENST00000506714.5 linkuse as main transcript	n.855T>C		non_coding_transcript_exon_variant	7/8	2
HERC6	ENST00000515365.1 linkuse as main transcript	n.423T>C		splice_region_variant, non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

56673

AN:

151966

Hom.:

15530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.730

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.700

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.316

AC:

68228

AN:

216168

Hom.:

15551

AF XY:

0.308

AC XY:

35903

AN XY:

116630

show subpopulations

Gnomad AFR exome

AF:

0.748

Gnomad AMR exome

AF:

0.427

Gnomad ASJ exome

AF:

0.164

Gnomad EAS exome

AF:

0.710

Gnomad SAS exome

AF:

0.474

Gnomad FIN exome

AF:

0.264

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.209

AC:

298353

AN:

1426826

Hom.:

48884

Cov.:

AF XY:

0.215

AC XY:

152395

AN XY:

708330

show subpopulations

Gnomad4 AFR exome

AF:

0.753

Gnomad4 AMR exome

AF:

0.422

Gnomad4 ASJ exome

AF:

0.161

Gnomad4 EAS exome

AF:

0.728

Gnomad4 SAS exome

AF:

0.475

Gnomad4 FIN exome

AF:

0.261

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.254

GnomAD4 genome

AF:

0.373

AC:

56793

AN:

152086

Hom.:

15581

Cov.:

AF XY:

0.383

AC XY:

28461

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.731

Gnomad4 AMR

AF:

0.368

Gnomad4 ASJ

AF:

0.167

Gnomad4 EAS

AF:

0.700

Gnomad4 SAS

AF:

0.505

Gnomad4 FIN

AF:

0.260

Gnomad4 NFE

AF:

0.156

Gnomad4 OTH

AF:

0.324

Alfa

AF:

0.210

Hom.:

6638

Bravo

AF:

0.396

TwinsUK

AF:

0.143

AC:

531

ALSPAC

AF:

0.142

AC:

546

ESP6500AA

AF:

0.716

AC:

2599

ESP6500EA

AF:

0.147

AC:

1194

ExAC

AF:

0.309

AC:

37207

Asia WGS

AF:

0.563

AC:

1953

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.3

DANN

Benign

0.60

DEOGEN2

Benign

0.0017

.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0000010

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.058

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.051

MutPred

0.42

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MPC

0.18

ClinPred

0.00030

GERP RS

2.6

Varity_R

0.041

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over