19-10096071-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031917.3(ANGPTL6):​c.493C>T​(p.Arg165Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000135 in 1,485,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.188992).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANGPTL6NM_031917.3 linkuse as main transcriptc.493C>T p.Arg165Cys missense_variant 2/6 ENST00000253109.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANGPTL6ENST00000253109.5 linkuse as main transcriptc.493C>T p.Arg165Cys missense_variant 2/61 NM_031917.3 P1
ANGPTL6ENST00000592641.5 linkuse as main transcriptc.493C>T p.Arg165Cys missense_variant 2/61 P1
ANGPTL6ENST00000589181.5 linkuse as main transcriptc.493C>T p.Arg165Cys missense_variant 1/55
ANGPTL6ENST00000586910.1 linkuse as main transcriptn.61C>T non_coding_transcript_exon_variant 1/24

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151976
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.50e-7
AC:
1
AN:
1333432
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
662192
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:
0.0000273
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151976
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2023The c.493C>T (p.R165C) alteration is located in exon 2 (coding exon 1) of the ANGPTL6 gene. This alteration results from a C to T substitution at nucleotide position 493, causing the arginine (R) at amino acid position 165 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.031
T;T;T
Eigen
Benign
0.049
Eigen_PC
Benign
0.067
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.86
D;.;T
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
2.0
.;M;M
MutationTaster
Benign
0.98
D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-2.0
.;.;N
REVEL
Benign
0.10
Sift
Benign
0.053
.;.;T
Sift4G
Uncertain
0.053
T;T;T
Polyphen
0.98
.;D;D
Vest4
0.36
MVP
0.66
ClinPred
0.43
T
GERP RS
4.3
Varity_R
0.17
gMVP
0.41

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.

Other links and lift over

dbSNP: rs1271967962; hg19: chr19-10206747; API