Genetic Variant NM_001330723.2:c.848A>T (chr1-151662212-A-T) – 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_001330723.2(SNX27):c.848A>T(p.Asp283Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D283G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SNX27
NM_001330723.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.20

Publications

0 publications found

Variant links:

Genes affected

SNX27 (HGNC:20073): (sorting nexin 27) This gene encodes a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). A highly similar protein in mouse is responsible for the specific recruitment of an isoform of serotonin 5-hydroxytryptamine 4 receptor into early endosomes, suggesting the analogous role for the human protein. [provided by RefSeq, Jul 2008]

SNX27 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, 0.898

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330723.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SNX27	NM_001330723.2	MANE Select	c.848A>T	p.Asp283Val	missense	Exon 5 of 12	NP_001317652.1
SNX27	NM_030918.6		c.848A>T	p.Asp283Val	missense	Exon 5 of 12	NP_112180.4
SNX27	NM_001437601.1		c.545A>T	p.Asp182Val	missense	Exon 4 of 11	NP_001424530.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SNX27	ENST00000458013.7	TSL:5 MANE Select	c.848A>T	p.Asp283Val	missense	Exon 5 of 12	ENSP00000400333.2
SNX27	ENST00000368843.8	TSL:1	c.848A>T	p.Asp283Val	missense	Exon 5 of 12	ENSP00000357836.3
SNX27	ENST00000368838.2	TSL:1	c.443A>T	p.Asp148Val	missense	Exon 4 of 10	ENSP00000357831.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251280

AF XY:

0.00000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111766

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

0.42

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.6

PhyloP100

8.2

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.65

Gain of catalytic residue at D283 (P = 0.0086)

MVP

0.83

MPC

1.8

ClinPred

1.0

GERP RS

5.5

Varity_R

0.87

gMVP

0.77

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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