11-65038733-A-C

Position:

chr11-65038733-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_013306.5(SNX15):c.826A>C(p.Ile276Leu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SNX15
NM_013306.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

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]

SNX15 links:

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]

ARL2-SNX15 links:

SNX15 (HGNC:):

SNX15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37747413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX15	NM_013306.5 linkuse as main transcript	c.826A>C	p.Ile276Leu	missense_variant	7/8	ENST00000377244.8	NP_037438.2	Q9NRS6-1E5KQS5
SNX15	NM_147777.4 linkuse as main transcript	c.665-953A>C		intron_variant			NP_680086.2	Q9NRS6-2
ARL2-SNX15	NR_037650.2 linkuse as main transcript	n.1433A>C		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SNX15	ENST00000377244.8 linkuse as main transcript	c.826A>C	p.Ile276Leu	missense_variant	7/8	1	NM_013306.5	ENSP00000366452.3	Q9NRS6-1
ARL2-SNX15	ENST00000301886.3 linkuse as main transcript	n.*1043A>C		non_coding_transcript_exon_variant	10/11	2		ENSP00000476630.1	V9GYD0
ARL2-SNX15	ENST00000301886.3 linkuse as main transcript	n.*1043A>C		3_prime_UTR_variant	10/11	2		ENSP00000476630.1	V9GYD0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152148

Hom.:

Cov.:

FAILED QC

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000738

AC:

1068

AN:

1447384

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

512

AN XY:

719250

show subpopulations

Gnomad4 AFR exome

AF:

0.000960

Gnomad4 AMR exome

AF:

0.0000237

Gnomad4 ASJ exome

AF:

0.000311

Gnomad4 EAS exome

AF:

0.000229

Gnomad4 SAS exome

AF:

0.000307

Gnomad4 FIN exome

AF:

0.0000950

Gnomad4 NFE exome

AF:

0.000862

Gnomad4 OTH exome

AF:

0.000551

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

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:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.826A>C (p.I276L) alteration is located in exon 7 (coding exon 7) of the SNX15 gene. This alteration results from a A to C substitution at nucleotide position 826, causing the isoleucine (I) at amino acid position 276 to be replaced by a leucine (L). 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

0.31

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

0.099

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

M_CAP

Benign

0.055

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.5

PROVEAN

Benign

-1.4

REVEL

Benign

0.29

Sift

Benign

0.10

Sift4G

Benign

0.34

Polyphen

0.38

Vest4

0.32

MutPred

0.70

Gain of disorder (P = 0.0453);

MVP

0.63

MPC

0.84

ClinPred

0.81

GERP RS

5.5

Varity_R

0.20

gMVP

0.28

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over