Genetic Variant ANGPTL8:p.Pro27Ser (chr19-11239716-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018687.7(ANGPTL8):c.79C>T(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ANGPTL8
NM_018687.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.175

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042853504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL8	NM_018687.7 link	c.79C>T	p.Pro27Ser	missense_variant	Exon 1 of 4	ENST00000252453.12	NP_061157.3	Q6UXH0
DOCK6	NM_020812.4 link	c.1644-1412G>A		intron_variant	Intron 14 of 47	ENST00000294618.12	NP_065863.2	Q96HP0B7Z9U8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL8	ENST00000252453.12 link	c.79C>T	p.Pro27Ser	missense_variant	Exon 1 of 4	1	NM_018687.7	ENSP00000252453.7		Q6UXH0
DOCK6	ENST00000294618.12 link	c.1644-1412G>A		intron_variant	Intron 14 of 47	1	NM_020812.4	ENSP00000294618.6		Q96HP0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247628

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134724

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461232

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.15

DANN

Benign

0.65

DEOGEN2

Benign

0.0043

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.34

T;.

M_CAP

Benign

0.0041

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.60

.;N

REVEL

Benign

0.0040

Sift

Benign

0.10

.;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0010

B;B

Vest4

0.025

MutPred

0.21

Gain of phosphorylation at P27 (P = 0.0736);Gain of phosphorylation at P27 (P = 0.0736);

MVP

0.061

MPC

0.20

ClinPred

0.13

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.029

gMVP

0.34

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