2-237578036-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_022449.4(RAB17):​c.277G>A​(p.Ala93Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,888 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RAB17
NM_022449.4 missense

Scores

1
15
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.80
Variant links:
Genes affected
RAB17 (HGNC:16523): (RAB17, member RAS oncogene family) The Rab subfamily of small GTPases plays an important role in the regulation of membrane trafficking. RAB17 is an epithelial cell-specific GTPase (Lutcke et al., 1993 [PubMed 8486736]).[supplied by OMIM, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAB17NM_022449.4 linkc.277G>A p.Ala93Thr missense_variant Exon 3 of 6 ENST00000264601.8 NP_071894.1 Q9H0T7-1A0A024R4A4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAB17ENST00000264601.8 linkc.277G>A p.Ala93Thr missense_variant Exon 3 of 6 1 NM_022449.4 ENSP00000264601.3 Q9H0T7-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250830
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135582
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459658
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
725698
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000540
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.277G>A (p.A93T) alteration is located in exon 3 (coding exon 2) of the RAB17 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the alanine (A) at amino acid position 93 to be replaced by a threonine (T). 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
Uncertain
0.41
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D;D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.063
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Uncertain
2.8
M;.
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.015
D;.
Polyphen
1.0
D;.
Vest4
0.67
MutPred
0.82
Loss of methylation at R89 (P = 0.1227);.;
MVP
0.88
MPC
0.41
ClinPred
0.97
D
GERP RS
4.4
Varity_R
0.63
gMVP
0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200859666; hg19: chr2-238486679; API