Genetic Variant ANGPTL8:p.Arg59Trp (chr19-11239812-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_018687.7(ANGPTL8):c.175C>T(p.Arg59Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,604,966 control chromosomes in the GnomAD database, including 6,838 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 ( 1237 hom., cov: 32)

Exomes 𝑓: 0.062 ( 5601 hom. )

Consequence

ANGPTL8
NM_018687.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.623

Publications

96 publications found

Variant links:

Genes affected

ANGPTL8 (HGNC:24933): (angiopoietin like 8) Predicted to enable hormone activity. Involved in regulation of lipid metabolic process and triglyceride homeostasis. Acts upstream of or within positive regulation of protein processing and regulation of lipoprotein metabolic process. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ANGPTL8 links:

DOCK6 (HGNC:19189): (dedicator of cytokinesis 6) This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2. [provided by RefSeq, Dec 2011]

DOCK6 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Adams-Oliver syndrome 2
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

DOCK6 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 (MetaRNN=0.0037017763).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL8	NM_018687.7 link	c.175C>T	p.Arg59Trp	missense_variant	Exon 1 of 4	ENST00000252453.12	NP_061157.3
DOCK6	NM_020812.4 link	c.1644-1508G>A		intron_variant	Intron 14 of 47	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL8	ENST00000252453.12 link	c.175C>T	p.Arg59Trp	missense_variant	Exon 1 of 4	1	NM_018687.7	ENSP00000252453.7
DOCK6	ENST00000294618.12 link	c.1644-1508G>A		intron_variant	Intron 14 of 47	1	NM_020812.4	ENSP00000294618.6

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16151

AN:

152050

Hom.:

1239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.252

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.0644

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0432

Gnomad OTH

AF:

0.0952

GnomAD2 exomes

AF:

0.113

AC:

25993

AN:

230988

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.265

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.0650

Gnomad NFE exome

AF:

0.0432

Gnomad OTH exome

AF:

0.0805

GnomAD4 exome

AF:

0.0622

AC:

90311

AN:

1452798

Hom.:

5601

Cov.:

AF XY:

0.0641

AC XY:

46277

AN XY:

722036

show subpopulations

African (AFR)

AF:

0.190

AC:

6324

AN:

33340

American (AMR)

AF:

0.250

AC:

10625

AN:

42488

Ashkenazi Jewish (ASJ)

AF:

0.0217

AC:

562

AN:

25882

East Asian (EAS)

AF:

0.261

AC:

10271

AN:

39278

South Asian (SAS)

AF:

0.147

AC:

12521

AN:

84982

European-Finnish (FIN)

AF:

0.0650

AC:

3429

AN:

52768

Middle Eastern (MID)

AF:

0.0760

AC:

437

AN:

5750

European-Non Finnish (NFE)

AF:

0.0378

AC:

41886

AN:

1108220

Other (OTH)

AF:

0.0708

AC:

4256

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5202

10403

15605

20806

26008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1834

3668

5502

7336

9170

<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:

0.106

AC:

16177

AN:

152168

Hom.:

1237

Cov.:

AF XY:

0.112

AC XY:

8364

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.177

AC:

7340

AN:

41504

American (AMR)

AF:

0.185

AC:

2820

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3472

East Asian (EAS)

AF:

0.252

AC:

1302

AN:

5170

South Asian (SAS)

AF:

0.155

AC:

749

AN:

4822

European-Finnish (FIN)

AF:

0.0644

AC:

682

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0433

AC:

2942

AN:

68002

Other (OTH)

AF:

0.0942

AC:

199

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

717

1434

2150

2867

3584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0632

Hom.:

1614

Bravo

AF:

0.120

TwinsUK

AF:

0.0405

AC:

150

ALSPAC

AF:

0.0363

AC:

140

ESP6500AA

AF:

0.171

AC:

673

ESP6500EA

AF:

0.0482

AC:

399

ExAC

AF:

0.104

AC:

12541

Asia WGS

AF:

0.163

AC:

570

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

T;T

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.77

T;.

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.

PhyloP100

0.62

PROVEAN

Benign

0.0

.;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

D;D

Vest4

0.12

ClinPred

0.030

GERP RS

3.5

PromoterAI

0.024

Neutral

(source)

Varity_R

0.31

gMVP

0.80

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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