chr11-65035158-C-G

Position:

• chr11-65035158-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013306.5(SNX15):​c.472C>G​(p.Gln158Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,438,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SNX15 NM_013306.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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]

SNX15 (HGNC:):

ACMG classification

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=0.089027524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX15	NM_013306.5	c.472C>G	p.Gln158Glu	missense_variant	5/8	ENST00000377244.8	NP_037438.2
SNX15	NM_147777.4	c.472C>G	p.Gln158Glu	missense_variant	5/7		NP_680086.2
ARL2-SNX15	NR_037650.2	n.1079C>G		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX15	ENST00000377244.8	c.472C>G	p.Gln158Glu	missense_variant	5/8	1	NM_013306.5	ENSP00000366452.3
ARL2-SNX15	ENST00000301886.3	n.*689C>G		non_coding_transcript_exon_variant	8/11	2		ENSP00000476630.1
ARL2-SNX15	ENST00000301886.3	n.*689C>G		3_prime_UTR_variant	8/11	2		ENSP00000476630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438208 Hom.: 0 Cov.: 37 AF XY: 0.00000280 AC XY: 2 AN XY: 713588

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: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.472C>G (p.Q158E) alteration is located in exon 5 (coding exon 5) of the SNX15 gene. This alteration results from a C to G substitution at nucleotide position 472, causing the glutamine (Q) at amino acid position 158 to be replaced by a glutamic acid (E). 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	0.069
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.;L
PROVEAN	Benign	0.020	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.23	B;.;.;.
Vest4		0.28
MutPred		0.22		Gain of helix (P = 0.0093);.;.;Gain of helix (P = 0.0093);
MVP		0.30
MPC		0.28
ClinPred		0.35	T
GERP RS		5.3
Varity_R		0.094
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-64802630;