Genetic Variant NM_014748.4:c.530G>A (chr2-27374352-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014748.4(SNX17):c.530G>A(p.Arg177Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R177W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SNX17
NM_014748.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.41

Publications

0 publications found

Variant links:

Genes affected

SNX17 (HGNC:14979): (sorting nexin 17) 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. This protein does not contain a coiled coil region, like some family members, but contains a B41 domain. This protein interacts with the cytoplasmic domain of P-selectin, and may function in the intracellular trafficking of P-selectin. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2012]

SNX17 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNX17	NM_014748.4 link	c.530G>A	p.Arg177Gln	missense_variant	Exon 7 of 15	ENST00000233575.7	NP_055563.1	Q15036-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX17	ENST00000233575.7 link	c.530G>A	p.Arg177Gln	missense_variant	Exon 7 of 15	1	NM_014748.4	ENSP00000233575.2		Q15036-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250942

AF XY:

0.0000221

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461118

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111424

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.530G>A (p.R177Q) alteration is located in exon 7 (coding exon 7) of the SNX17 gene. This alteration results from a G to A substitution at nucleotide position 530, causing the arginine (R) at amino acid position 177 to be replaced by a glutamine (Q). 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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

8.4

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

.;D

Vest4

0.97

MutPred

0.52

.;Gain of ubiquitination at K178 (P = 0.102);

MVP

0.86

MPC

0.81

ClinPred

0.93

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.78

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_014748.4:c.530G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over