chr11-65032452-A-G

Variant names:

• chr11-65032452-A-G
• NM_013306.5:c.157A>G

Variant summary

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

The NM_013306.5(SNX15):​c.157A>G​(p.Ser53Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNX15 NM_013306.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

Genes affected

SNX15 (HGNC:14978): (sorting nexin 15) 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. Overexpression of this gene results in a decrease in the processing of insulin and hepatocyte growth factor receptors to their mature subunits. This decrease is caused by the mislocalization of furin, the endoprotease responsible for cleavage of insulin and hepatocyte growth factor receptors. This protein is involved in endosomal trafficking from the plasma membrane to recycling endosomes or the trans-Golgi network. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ADP-ribosylation factor-like 2 (ARL2) gene. [provided by RefSeq, Dec 2010]

ARL2-SNX15 (HGNC:49197): (ARL2-SNX15 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring ADP-ribosylation factor-like 2 (ARL2) and sorting nexin 15 (SNX15) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity SNX15_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNX15	NM_013306.5	c.157A>G	p.Ser53Gly	missense_variant	Exon 3 of 8	ENST00000377244.8	NP_037438.2
SNX15	NM_147777.4	c.157A>G	p.Ser53Gly	missense_variant	Exon 3 of 7		NP_680086.2
ARL2-SNX15	NR_037650.2	n.764A>G		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX15	ENST00000377244.8	c.157A>G	p.Ser53Gly	missense_variant	Exon 3 of 8	1	NM_013306.5	ENSP00000366452.3
ARL2-SNX15	ENST00000301886.3	n.*374A>G		non_coding_transcript_exon_variant	Exon 6 of 11	2		ENSP00000476630.1
ARL2-SNX15	ENST00000301886.3	n.*374A>G		3_prime_UTR_variant	Exon 6 of 11	2		ENSP00000476630.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 54 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

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 specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157A>G (p.S53G) alteration is located in exon 3 (coding exon 3) of the SNX15 gene. This alteration results from a A to G substitution at nucleotide position 157, causing the serine (S) at amino acid position 53 to be replaced by a glycine (G). 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	Uncertain	0.45
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Pathogenic	3.5	M;.;.;M
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.63
MutPred		0.66		Loss of sheet (P = 0.0315);.;.;Loss of sheet (P = 0.0315);
MVP		0.60
MPC		0.87
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.65
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64799924;