Genetic Variant NM_017912.4:c.1027T>G (chr4-88398144-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017912.4(HERC6):c.1027T>G(p.Phe343Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,582,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HERC6
NM_017912.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.330

Publications

26 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08285305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017912.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC6	NM_017912.4	MANE Select	c.1027T>G	p.Phe343Val	missense splice_region	Exon 8 of 23	NP_060382.3
	HERC6	NM_001165136.2		c.1027T>G	p.Phe343Val	missense splice_region	Exon 8 of 22	NP_001158608.1	Q8IVU3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HERC6	ENST00000264346.12	TSL:1 MANE Select	c.1027T>G	p.Phe343Val	missense splice_region	Exon 8 of 23	ENSP00000264346.8	Q8IVU3-1
HERC6	ENST00000380265.9	TSL:1	c.1027T>G	p.Phe343Val	missense splice_region	Exon 8 of 22	ENSP00000369617.5	Q8IVU3-2
HERC6	ENST00000896956.1		c.1027T>G	p.Phe343Val	missense splice_region	Exon 8 of 24	ENSP00000567015.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

216168

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000231

AC:

AN:

1430642

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

710170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32464

American (AMR)

AF:

0.00

AC:

AN:

40064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25650

East Asian (EAS)

AF:

0.00

AC:

AN:

38608

South Asian (SAS)

AF:

0.00

AC:

AN:

80672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000292

AC:

AN:

1095740

Other (OTH)

AF:

0.0000169

AC:

AN:

59272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41362

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

14006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0025

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.52

M_CAP

Benign

0.0028

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.33

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.36

REVEL

Benign

0.068

Sift

Benign

0.20

Sift4G

Benign

0.24

Polyphen

0.038

Vest4

0.17

MutPred

0.43

Loss of sheet (P = 0.0457)

MVP

0.85

MPC

0.20

ClinPred

0.093

GERP RS

2.6

Varity_R

0.063

gMVP

0.25

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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