3-128807625-A-T

Position:

• chr3-128807625-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_004637.6(RAB7A):​c.482A>T​(p.Asn161Ile) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N161T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB7A NM_004637.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U: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 Pathogenic. Variant got 13 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128807625-A-C is described in Lovd as [Pathogenic].
• 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, 0.978
• PP5: Variant 3-128807625-A-T is Pathogenic according to our data. Variant chr3-128807625-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 637404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB7A	NM_004637.6	c.482A>T	p.Asn161Ile	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>T	p.Asn161Ile	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: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2020

This variant has been observed in individual(s) with Charcot Marie Tooth disease (PMID: 24498653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 637404). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 161 of the RAB7A protein (p.Asn161Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant has been reported to affect RAB7A protein function (PMID: 29130394). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn161 amino acid residue in RAB7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23188822, 15455439, 24498653, 18272684, 26791407). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.1	D;D;N;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;T;D
Polyphen		0.98	D;D;.;.
Vest4		0.96
MutPred		0.91		Gain of methylation at K157 (P = 0.0719);.;.;.;
MVP		0.93
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.94

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;