1-151662221-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001330723.2(SNX27):​c.857C>T​(p.Thr286Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T286K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SNX27
NM_001330723.2 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94
Variant links:
Genes affected
SNX27 (HGNC:20073): (sorting nexin 27) This gene encodes a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). A highly similar protein in mouse is responsible for the specific recruitment of an isoform of serotonin 5-hydroxytryptamine 4 receptor into early endosomes, suggesting the analogous role for the human protein. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35102832).
BS2
High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SNX27NM_001330723.2 linkc.857C>T p.Thr286Met missense_variant Exon 5 of 12 ENST00000458013.7 NP_001317652.1 Q96L92-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SNX27ENST00000458013.7 linkc.857C>T p.Thr286Met missense_variant Exon 5 of 12 5 NM_001330723.2 ENSP00000400333.2 Q96L92-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152052
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251184
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135776
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461342
Hom.:
0
Cov.:
30
AF XY:
0.0000206
AC XY:
15
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000306
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152052
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74274
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:
0.0000294
Gnomad4 OTH
AF:
0.00
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

Severe myoclonic epilepsy in infancy Uncertain:1
May 21, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 573756). This variant has not been reported in the literature in individuals affected with SNX27-related conditions. This variant is present in population databases (rs540042464, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 286 of the SNX27 protein (p.Thr286Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
.;.;T
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
1.7
.;L;L
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.1
.;N;N
REVEL
Benign
0.12
Sift
Benign
0.063
.;T;T
Sift4G
Benign
0.13
.;T;T
Polyphen
0.98, 0.98
.;D;D
Vest4
0.65, 0.63
MutPred
0.23
.;Loss of glycosylation at T286 (P = 0.0309);Loss of glycosylation at T286 (P = 0.0309);
MVP
0.11
MPC
1.4
ClinPred
0.80
D
GERP RS
5.5
Varity_R
0.16
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs540042464; hg19: chr1-151634697; COSMIC: COSV100919033; COSMIC: COSV100919033; API