chr11-65035150-G-T

Variant names:

• chr11-65035150-G-T
• rs780682677
• NM_013306.5:c.464G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013306.5(SNX15):​c.464G>T​(p.Arg155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000726 in 137,798 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. R155Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNX15 NM_013306.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044751704).

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.464G>T	p.Arg155Leu	missense	Exon 5 of 8	NP_037438.2
	SNX15	NM_147777.4		c.464G>T	p.Arg155Leu	missense	Exon 5 of 7	NP_680086.2
	ARL2-SNX15	NR_037650.2		n.1071G>T		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX15	ENST00000377244.8	TSL:1 MANE Select	c.464G>T	p.Arg155Leu	missense	Exon 5 of 8	ENSP00000366452.3	Q9NRS6-1
	ARL2-SNX15	ENST00000301886.3	TSL:2	n.*681G>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000476630.1	V9GYD0
	ARL2-SNX15	ENST00000301886.3	TSL:2	n.*681G>T		3_prime_UTR	Exon 8 of 11	ENSP00000476630.1	V9GYD0

Frequencies

GnomAD3 genomes AF: 0.00000726 AC: 1 AN: 137798 Hom.: 0 Cov.: 31

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000159

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1043504 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 521728

African (AFR) AF: 0.00 AC: 0 AN: 23756

American (AMR) AF: 0.00 AC: 0 AN: 33784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16560

East Asian (EAS) AF: 0.00 AC: 0 AN: 18708

South Asian (SAS) AF: 0.00 AC: 0 AN: 76262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3848

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 799944

Other (OTH) AF: 0.00 AC: 0 AN: 39262

GnomAD4 genome AF: 0.00000726 AC: 1 AN: 137798 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 66818

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38360

American (AMR) AF: 0.00 AC: 0 AN: 14112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3256

East Asian (EAS) AF: 0.00 AC: 0 AN: 4114

South Asian (SAS) AF: 0.00 AC: 0 AN: 3728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000159 AC: 1 AN: 62952

Other (OTH) AF: 0.00 AC: 0 AN: 1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.16
PROVEAN	Benign	1.2	N
REVEL	Benign	0.035
Sift	Benign	0.58	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.29		Gain of helix (P = 0.0164)
MVP		0.20
MPC		0.32
ClinPred		0.11	T
GERP RS		-2.0
Varity_R		0.030
gMVP		0.40
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs780682677; hg19: chr11-64802622;