19-10094898-C-T

Variant summary

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

The NM_031917.3(ANGPTL6):​c.623G>A​(p.Arg208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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: 0.000014 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.907
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=0.13065541).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANGPTL6NM_031917.3 linkuse as main transcriptc.623G>A p.Arg208His missense_variant 3/6 ENST00000253109.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANGPTL6ENST00000253109.5 linkuse as main transcriptc.623G>A p.Arg208His missense_variant 3/61 NM_031917.3 P1
ANGPTL6ENST00000592641.5 linkuse as main transcriptc.623G>A p.Arg208His missense_variant 3/61 P1
ANGPTL6ENST00000589181.5 linkuse as main transcriptc.623G>A p.Arg208His missense_variant 2/55
ANGPTL6ENST00000586910.1 linkuse as main transcriptn.191G>A non_coding_transcript_exon_variant 2/24

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
32
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:
0.00000400
AC:
1
AN:
249800
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135256
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:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1460936
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
726734
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74334
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:
0.0000189
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 14, 2023The c.623G>A (p.R208H) alteration is located in exon 3 (coding exon 2) of the ANGPTL6 gene. This alteration results from a G to A substitution at nucleotide position 623, causing the arginine (R) at amino acid position 208 to be replaced by a histidine (H). 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
0.064
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
18
DANN
Benign
0.69
DEOGEN2
Benign
0.0035
T;T;T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.097
N
LIST_S2
Benign
0.68
T;.;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.26
.;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.020
.;.;N
REVEL
Benign
0.043
Sift
Benign
0.34
.;.;T
Sift4G
Benign
0.16
T;T;T
Polyphen
0.47
.;P;P
Vest4
0.13
MutPred
0.41
Gain of glycosylation at S212 (P = 0.0728);Gain of glycosylation at S212 (P = 0.0728);Gain of glycosylation at S212 (P = 0.0728);
MVP
0.58
ClinPred
0.17
T
GERP RS
3.2
Varity_R
0.050
gMVP
0.30

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: rs780461920; hg19: chr19-10205574; API