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rs3135506

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001371904.1(APOA5):c.56C>T(p.Ser19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152214 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. S19W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.58

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
?
Computational evidence support a benign effect (MetaRNN=0.16997331).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APOA5NM_001371904.1 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 2/3 ENST00000227665.9
APOA5NM_001166598.2 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 3/4
APOA5NM_052968.5 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 3/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOA5ENST00000227665.9 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 2/31 NM_001371904.1 P1
APOA5ENST00000433069.2 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 3/41 P1
APOA5ENST00000673688.1 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 2/3
APOA5ENST00000542499.5 linkuse as main transcriptc.56C>T p.Ser19Leu missense_variant 3/45 P1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000217
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
GnomAD3 exomes
AF:
0.0000295
AC:
7
AN:
237114
Hom.:
0
AF XY:
0.0000234
AC XY:
3
AN XY:
128364
show subpopulations
Gnomad AFR exome
AF:
0.000333
Gnomad AMR exome
AF:
0.0000604
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000824
AC:
12
AN:
1455540
Hom.:
0
AF XY:
0.00000691
AC XY:
5
AN XY:
723566
show subpopulations
Gnomad4 AFR exome
AF:
0.000270
Gnomad4 AMR exome
AF:
0.0000458
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
Bravo
AF:
0.000110
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 27, 2022This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 19 of the APOA5 protein (p.Ser19Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with APOA5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 26, 2020The p.S19L variant (also known as c.56C>T), located in coding exon 2 of the APOA5 gene, results from a C to T substitution at nucleotide position 56. The serine at codon 19 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.32
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;T;.
Eigen
Benign
-0.083
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.59
D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
2.0
M;M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.21
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.015
D;D;T
Polyphen
0.67
P;P;.
Vest4
0.22
MutPred
0.31
Loss of glycosylation at S19 (P = 0.0581);Loss of glycosylation at S19 (P = 0.0581);Loss of glycosylation at S19 (P = 0.0581);
MVP
0.91
MPC
0.51
ClinPred
0.063
T
GERP RS
5.4
Varity_R
0.084
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs3135506; hg19: chr11-116662407; COSMIC: COSV57062583; COSMIC: COSV57062583; API