rs775224639

Variant names:

• chr8-81801564-C-T
• rs775224639
• NM_152836.3:c.968G>A

Variant summary

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

The NM_152836.3(SNX16):​c.968G>A​(p.Ser323Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000528 in 1,515,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S323G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SNX16 NM_152836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.980
• Publications: 0 publications found

Genes affected

SNX16 (HGNC:14980): (sorting nexin 16) 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. The protein encoded by this gene associates with late endosome membranes as is involved in tubule formation, cholesterol transport, and transport of tetraspanin CD81. The encoded protein also inhibits cell migration and tumorigenesis. [provided by RefSeq, Jan 2017]

ENSG00000253334 (HGNC:):

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=0.063684046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152836.3. 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
	SNX16	NM_152836.3	MANE Select	c.968G>A	p.Ser323Asn	missense	Exon 8 of 8	NP_690049.1	P57768-1
	SNX16	NM_022133.4		c.968G>A	p.Ser323Asn	missense	Exon 9 of 9	NP_071416.2
	SNX16	NM_001348189.2		c.881G>A	p.Ser294Asn	missense	Exon 10 of 10	NP_001335118.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX16	ENST00000345957.9	TSL:1 MANE Select	c.968G>A	p.Ser323Asn	missense	Exon 8 of 8	ENSP00000322652.4	P57768-1
	SNX16	ENST00000353788.8	TSL:1	c.881G>A	p.Ser294Asn	missense	Exon 7 of 7	ENSP00000322631.4	P57768-2
	SNX16	ENST00000396330.6	TSL:5	c.968G>A	p.Ser323Asn	missense	Exon 9 of 9	ENSP00000379621.2	P57768-1

Frequencies

GnomAD3 genomes AF: 0.0000145 AC: 2 AN: 137890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000156

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000177 AC: 4 AN: 225778 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000320

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: 0.00000436 AC: 6 AN: 1377710 Hom.: 0 Cov.: 30 AF XY: 0.00000581 AC XY: 4 AN XY: 687970

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

African (AFR) AF: 0.00 AC: 0 AN: 31246

American (AMR) AF: 0.0000239 AC: 1 AN: 41764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24668

East Asian (EAS) AF: 0.00 AC: 0 AN: 36542

South Asian (SAS) AF: 0.0000486 AC: 4 AN: 82254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058360

Other (OTH) AF: 0.0000176 AC: 1 AN: 56876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00504866), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000145 AC: 2 AN: 137890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 65850

African (AFR) AF: 0.00 AC: 0 AN: 37280

American (AMR) AF: 0.000156 AC: 2 AN: 12812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4630

South Asian (SAS) AF: 0.00 AC: 0 AN: 4328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65074

Other (OTH) AF: 0.00 AC: 0 AN: 1878

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.98
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.042
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.094
MutPred		0.11		Loss of phosphorylation at S323 (P = 0.0239)
MVP		0.43
MPC		0.22
ClinPred		0.049	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.11
Mutation Taster		=96/4	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: rs775224639; hg19: chr8-82713799;