19-10093552-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.1019G>A​(p.Arg340His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,868 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 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ANGPTL6
NM_031917.3 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38
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=0.14259148).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANGPTL6NM_031917.3 linkuse as main transcriptc.1019G>A p.Arg340His missense_variant 5/6 ENST00000253109.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANGPTL6ENST00000253109.5 linkuse as main transcriptc.1019G>A p.Arg340His missense_variant 5/61 NM_031917.3 P1
ANGPTL6ENST00000592641.5 linkuse as main transcriptc.1019G>A p.Arg340His missense_variant 5/61 P1
ANGPTL6ENST00000589181.5 linkuse as main transcriptc.899G>A p.Arg300His missense_variant 4/55

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000640
AC:
16
AN:
250124
Hom.:
0
AF XY:
0.0000886
AC XY:
12
AN XY:
135374
show subpopulations
Gnomad AFR exome
AF:
0.0000622
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000974
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000486
AC:
71
AN:
1461634
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000531
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.000147
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

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 GeneticsApr 20, 2023The c.1019G>A (p.R340H) alteration is located in exon 5 (coding exon 4) of the ANGPTL6 gene. This alteration results from a G to A substitution at nucleotide position 1019, causing the arginine (R) at amino acid position 340 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
0.070
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.012
T;T;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.76
T;.;T
M_CAP
Uncertain
0.096
D
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
0.36
.;N;N
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.8
.;.;N
REVEL
Benign
0.25
Sift
Uncertain
0.0020
.;.;D
Sift4G
Benign
0.086
T;D;D
Polyphen
0.0090
.;B;B
Vest4
0.29
MVP
0.79
ClinPred
0.082
T
GERP RS
2.4
Varity_R
0.53
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.

Other links and lift over

dbSNP: rs367822624; hg19: chr19-10204228; API