7-26360992-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_013322.3(SNX10):c.42G>T(p.Trp14Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNX10 NM_013322.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

Genes affected

SNX10 (HGNC:14974): (sorting nexin 10) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members. This gene may play a role in regulating endosome homeostasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain PX (size 117) in uniprot entity SNX10_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_013322.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX10	NM_013322.3	c.42G>T	p.Trp14Cys	missense_variant	3/7	ENST00000338523.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX10	ENST00000338523.9	c.42G>T	p.Trp14Cys	missense_variant	3/7	1	NM_013322.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2020

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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SNX10-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 14 of the SNX10 protein (p.Trp14Cys). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;T;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;T;.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.79	N;.;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
REVEL	Benign	0.26
Sift4G	Benign	0.20	T;T;T;D;T;T
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.44
MutPred		0.57		.;Loss of MoRF binding (P = 0.0444);.;Loss of MoRF binding (P = 0.0444);.;.;
MVP		0.51
MPC		0.49
ClinPred		0.88	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.53

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

Other links and lift over

dbSNP: rs767247872; hg19: chr7-26400612;