rs121909080

Positions:

• chr3-128807625-A-C
• chr3-128807625-A-G
• chr3-128807625-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_004637.6(RAB7A):​c.482A>C​(p.Asn161Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB7A NM_004637.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: 8.57

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]

RAB7A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Ras-related protein Rab-7a (size 205) in uniprot entity RAB7A_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_004637.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAB7A. . Gene score misZ 2.2805 (greater than the threshold 3.09). Trascript score misZ 3.3657 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type 2B.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB7A	NM_004637.6	c.482A>C	p.Asn161Thr	missense_variant	5/6	ENST00000265062.8	NP_004628.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB7A	ENST00000265062.8	c.482A>C	p.Asn161Thr	missense_variant	5/6	1	NM_004637.6	ENSP00000265062.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease type 2B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2004

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D;D;N;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;T;T
Sift4G	Uncertain	0.0020	D;D;T;D
Polyphen		0.79	P;P;.;.
Vest4		0.93
MutPred		0.95		Gain of catalytic residue at Q164 (P = 0.0578);.;.;.;
MVP		0.88
MPC		1.7
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.85

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

Other links and lift over

dbSNP: rs121909080; hg19: chr3-128526468;