Genetic Variant SNX1:p.Pro16Thr (chr15-64096059-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_003099.5(SNX1):c.46C>A(p.Pro16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P16S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SNX1
NM_003099.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.47

Publications

0 publications found

Variant links:

Genes affected

SNX1 (HGNC:11172): (sorting nexin 1) 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 endosomal protein regulates the cell-surface expression of epidermal growth factor receptor. This protein also has a role in sorting protease-activated receptor-1 from early endosomes to lysosomes. This protein may form oligomeric complexes with family members. This gene results in three transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

SNX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003099.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNX1	NM_003099.5	MANE Select	c.46C>A	p.Pro16Thr	missense	Exon 1 of 15	NP_003090.2
SNX1	NM_001242933.2		c.46C>A	p.Pro16Thr	missense	Exon 1 of 15	NP_001229862.1	Q13596-3
SNX1	NM_148955.4		c.46C>A	p.Pro16Thr	missense	Exon 1 of 13	NP_683758.1	Q13596-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNX1	ENST00000559844.6	TSL:1 MANE Select	c.46C>A	p.Pro16Thr	missense	Exon 1 of 15	ENSP00000453785.1	Q13596-1
SNX1	ENST00000561026.5	TSL:1	c.46C>A	p.Pro16Thr	missense	Exon 1 of 13	ENSP00000453567.1	Q13596-2
SNX1	ENST00000380285.7	TSL:1	n.46C>A		non_coding_transcript_exon	Exon 1 of 15	ENSP00000369638.3	J3KPH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711756

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

39858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25570

East Asian (EAS)

AF:

0.00

AC:

AN:

38742

South Asian (SAS)

AF:

0.00

AC:

AN:

82834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102380

Other (OTH)

AF:

0.00

AC:

AN:

59564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.4

PhyloP100

3.5

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.44

MutPred

0.63

Gain of phosphorylation at P16 (P = 0.0085)

MVP

0.63

MPC

0.84

ClinPred

1.0

GERP RS

5.5

PromoterAI

0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.58

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over