7-2257418-C-T

Variant summary

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

The NM_013321.4(SNX8):​c.1081G>A​(p.Ala361Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A361S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SNX8
NM_013321.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95
Variant links:
Genes affected
SNX8 (HGNC:14972): (sorting nexin 8) Enables identical protein binding activity and phosphatidylinositol binding activity. Involved in early endosome to Golgi transport and intracellular protein transport. Located in early endosome membrane. Colocalizes with retromer complex. [provided by Alliance of Genome Resources, Apr 2022]
MIR6836 (HGNC:50067): (microRNA 6836) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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=0.12072092).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SNX8NM_013321.4 linkc.1081G>A p.Ala361Thr missense_variant Exon 9 of 11 ENST00000222990.8 NP_037453.1 Q9Y5X2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SNX8ENST00000222990.8 linkc.1081G>A p.Ala361Thr missense_variant Exon 9 of 11 1 NM_013321.4 ENSP00000222990.3 Q9Y5X2
SNX8ENST00000480807.1 linkn.201G>A non_coding_transcript_exon_variant Exon 1 of 3 2
SNX8ENST00000479689.1 linkn.*248G>A downstream_gene_variant 2
MIR6836ENST00000617724.1 linkn.*97G>A downstream_gene_variant 6

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000817
AC:
2
AN:
244670
Hom.:
0
AF XY:
0.00000751
AC XY:
1
AN XY:
133194
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000292
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:
0.00000905
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1458332
Hom.:
0
Cov.:
35
AF XY:
0.00000276
AC XY:
2
AN XY:
725572
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000595

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 26, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1081G>A (p.A361T) alteration is located in exon 9 (coding exon 9) of the SNX8 gene. This alteration results from a G to A substitution at nucleotide position 1081, causing the alanine (A) at amino acid position 361 to be replaced by a threonine (T). 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
0.074
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
16
DANN
Benign
0.86
DEOGEN2
Benign
0.0084
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.43
N
REVEL
Benign
0.055
Sift
Benign
0.35
T
Sift4G
Benign
0.36
T
Polyphen
0.28
B
Vest4
0.16
MutPred
0.20
Gain of phosphorylation at A361 (P = 0.031);
MVP
0.28
MPC
0.25
ClinPred
0.16
T
GERP RS
4.1
Varity_R
0.025
gMVP
0.12

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: rs746184528; hg19: chr7-2297053; API