chr11-65038587-G-A

Variant names:

• chr11-65038587-G-A
• rs369228727
• NM_013306.5:c.680G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013306.5(SNX15):​c.680G>A​(p.Ser227Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S227T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNX15 NM_013306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17109409).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013306.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX15	NM_013306.5	MANE Select	c.680G>A	p.Ser227Asn	missense	Exon 7 of 8	NP_037438.2
	SNX15	NM_147777.4		c.665-1099G>A		intron	N/A	NP_680086.2
	ARL2-SNX15	NR_037650.2		n.1287G>A		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX15	ENST00000377244.8	TSL:1 MANE Select	c.680G>A	p.Ser227Asn	missense	Exon 7 of 8	ENSP00000366452.3	Q9NRS6-1
	ARL2-SNX15	ENST00000301886.3	TSL:2	n.*897G>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000476630.1	V9GYD0
	ARL2-SNX15	ENST00000301886.3	TSL:2	n.*897G>A		3_prime_UTR	Exon 10 of 11	ENSP00000476630.1	V9GYD0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 214018 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414882 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 699252

African (AFR) AF: 0.00 AC: 0 AN: 32174

American (AMR) AF: 0.00 AC: 0 AN: 38786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39062

South Asian (SAS) AF: 0.00 AC: 0 AN: 79094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51702

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4670

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088286

Other (OTH) AF: 0.00 AC: 0 AN: 58226

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.4
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.024
Sift	Benign	0.091	T
Sift4G	Uncertain	0.025	D
Polyphen		0.53	P
Vest4		0.24
MutPred		0.28		Loss of glycosylation at S227 (P = 0.0079)
MVP		0.24
MPC		0.34
ClinPred		0.38	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.48
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs369228727; hg19: chr11-64806059;