chr3-128807614-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_004637.6(RAB7A):c.471G>T(p.Lys157Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Genomes: not found (cov: 32)
Consequence
RAB7A
NM_004637.6 missense
NM_004637.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 5.17
Genes affected
RAB7A (HGNC:9788): (RAB7A, member RAS oncogene family) RAB family members are small, RAS-related GTP-binding proteins that are important regulators of vesicular transport. Each RAB protein targets multiple proteins that act in exocytic / endocytic pathways. This gene encodes a RAB family member that regulates vesicle traffic in the late endosomes and also from late endosomes to lysosomes. This encoded protein is also involved in the cellular vacuolation of the VacA cytotoxin of Helicobacter pylori. Mutations at highly conserved amino acid residues in this gene have caused some forms of Charcot-Marie-Tooth (CMT) type 2 neuropathies. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004637.6
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RAB7A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
?
Variant 3-128807614-G-T is Pathogenic according to our data. Variant chr3-128807614-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 846631.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-128807614-G-T is described in UniProt as null. Variant chr3-128807614-G-T is described in UniProt as null. Variant chr3-128807614-G-T is described in UniProt as null. Variant chr3-128807614-G-T is described in UniProt as null.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAB7A | NM_004637.6 | c.471G>T | p.Lys157Asn | missense_variant | 5/6 | ENST00000265062.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAB7A | ENST00000265062.8 | c.471G>T | p.Lys157Asn | missense_variant | 5/6 | 1 | NM_004637.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2019 | This missense change has been reported to affect RAB7A protein function (PMID: 18501189, 21151572, 23179371, 23188822, 23458836, 24344282). For these reasons, this variant has been classified as Pathogenic. A different variant (c.471G>C) giving rise to the same protein effect observed here (p.Lys157Asn) has been determined to be pathogenic (PMID: 17060578). This suggests that this variant is also likely to be causative of disease. This variant has not been reported in the literature in individuals with RAB7A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 157 of the RAB7A protein (p.Lys157Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;.;.
Vest4
MutPred
Loss of ubiquitination at K157 (P = 0.011);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at