19-10096160-G-C

Position:

chr19-10096160-G-C

Variant summary

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

The NM_031917.3(ANGPTL6):c.404C>G(p.Ala135Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,315,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A135E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.631

Variant links:

Genes affected

ANGPTL6 (HGNC:23140): (angiopoietin like 6) Predicted to enable signaling receptor binding activity. Predicted to be involved in angiogenesis and cell differentiation. Located in extracellular exosome. Part of collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ANGPTL6 links:

Genome browser will be placed here

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=0.065095484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL6	NM_031917.3 linkuse as main transcript	c.404C>G	p.Ala135Gly	missense_variant	2/6	ENST00000253109.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ANGPTL6	ENST00000253109.5 linkuse as main transcript	c.404C>G	p.Ala135Gly	missense_variant	2/6	1	NM_031917.3	P1
ANGPTL6	ENST00000592641.5 linkuse as main transcript	c.404C>G	p.Ala135Gly	missense_variant	2/6	1		P1
ANGPTL6	ENST00000589181.5 linkuse as main transcript	c.404C>G	p.Ala135Gly	missense_variant	1/5	5
ANGPTL6	ENST00000586910.1 linkuse as main transcript			upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151348

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000722

AC:

AN:

13846

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

8648

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:

0.000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000533

AC:

AN:

1163918

Hom.:

Cov.:

AF XY:

0.0000462

AC XY:

AN XY:

562652

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000445

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000226

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000427

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151348

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73916

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:

0.0000591

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000398

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 135 of the ANGPTL6 protein (p.Ala135Gly). This variant is present in population databases (rs754807990, gnomAD 0.02%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with ANGPTL6-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.023

T;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.56

T;.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.0

.;.;N

REVEL

Benign

0.056

Sift

Uncertain

0.022

.;.;D

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0010

.;B;B

Vest4

0.12

MutPred

0.24

Loss of stability (P = 0.1009);Loss of stability (P = 0.1009);Loss of stability (P = 0.1009);

MVP

0.56

ClinPred

0.038

GERP RS

2.0

Varity_R

0.081

gMVP

0.19

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over