chr11-65038596-A-C

Position:

chr11-65038596-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013306.5(SNX15):c.689A>C(p.His230Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,580,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

SNX15
NM_013306.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06193608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX15	NM_013306.5 linkuse as main transcript	c.689A>C	p.His230Pro	missense_variant	7/8	ENST00000377244.8	NP_037438.2	Q9NRS6-1E5KQS5
SNX15	NM_147777.4 linkuse as main transcript	c.665-1090A>C		intron_variant			NP_680086.2	Q9NRS6-2
ARL2-SNX15	NR_037650.2 linkuse as main transcript	n.1296A>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.689A>C	p.His230Pro	missense_variant	7/8	1	NM_013306.5	ENSP00000366452.3	Q9NRS6-1
ARL2-SNX15	ENST00000301886.3 linkuse as main transcript	n.*906A>C		non_coding_transcript_exon_variant	10/11	2		ENSP00000476630.1	V9GYD0
ARL2-SNX15	ENST00000301886.3 linkuse as main transcript	n.*906A>C		3_prime_UTR_variant	10/11	2		ENSP00000476630.1	V9GYD0

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000268

AC:

AN:

224196

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

121246

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.0000985

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:

0.000534

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.000534

AC:

762

AN:

1427818

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

389

AN XY:

707074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000614

Gnomad4 AMR exome

AF:

0.0000990

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:

0.000673

Gnomad4 OTH exome

AF:

0.000340

GnomAD4 genome

AF:

0.000302

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000342

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000272

AC:

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

May 28, 2024

The c.689A>C (p.H230P) 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 689, causing the histidine (H) at amino acid position 230 to be replaced by a proline (P). 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

0.077

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.040

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.66

M_CAP

Benign

0.021

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Uncertain

0.026

Sift4G

Benign

0.35

Polyphen

0.63

Vest4

0.28

MVP

0.42

MPC

0.98

ClinPred

0.047

GERP RS

4.2

Varity_R

0.37

gMVP

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over