Genetic Variant ANGPTL6:p.Pro124Arg (chr19-10096193-G-C) – 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_031917.3(ANGPTL6):c.371C>G(p.Pro124Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P124L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.127

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intracranial berry aneurysm
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANGPTL6 links:

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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=0.09946257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL6	NM_031917.3 link	c.371C>G	p.Pro124Arg	missense_variant	Exon 2 of 6	ENST00000253109.5	NP_114123.2	Q8NI99A0A024R7A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANGPTL6	ENST00000253109.5 link	c.371C>G	p.Pro124Arg	missense_variant	Exon 2 of 6	1	NM_031917.3	ENSP00000253109.3	Q8NI99
ANGPTL6	ENST00000592641.5 link	c.371C>G	p.Pro124Arg	missense_variant	Exon 2 of 6	1		ENSP00000467930.1	Q8NI99
ANGPTL6	ENST00000589181.5 link	c.371C>G	p.Pro124Arg	missense_variant	Exon 1 of 5	5		ENSP00000465597.1	K7EKF6
ANGPTL6	ENST00000586910.1 link	n.-62C>G		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1089760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

517848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22542

American (AMR)

AF:

0.00

AC:

AN:

8096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14048

East Asian (EAS)

AF:

0.00

AC:

AN:

25794

South Asian (SAS)

AF:

0.00

AC:

AN:

25644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2914

European-Non Finnish (NFE)

AF:

0.00000216

AC:

AN:

925002

Other (OTH)

AF:

0.00

AC:

AN:

43590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

3.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0056

T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.33

T;.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;N

PhyloP100

-0.13

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.74

.;.;N

REVEL

Benign

0.034

Sift

Benign

0.092

.;.;T

Sift4G

Uncertain

0.048

D;T;T

Polyphen

0.20

.;B;B

Vest4

0.077

MutPred

0.26

Gain of methylation at P124 (P = 0.0058);Gain of methylation at P124 (P = 0.0058);Gain of methylation at P124 (P = 0.0058);

MVP

0.39

ClinPred

0.20

GERP RS

2.0

PromoterAI

-0.065

Neutral

(source)

Varity_R

0.026

gMVP

0.14

Mutation Taster

=85/15

polymorphism

(source)

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

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19-10096193-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over