rs121909080

Variant names:

• chr3-128807625-A-C
• rs121909080
• NM_004637.6:c.482A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N161D) has been classified as Likely pathogenic.

• 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
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2B

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain 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 chr3-128807624-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1041821.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 3-128807625-A-C is Pathogenic according to our data. Variant chr3-128807625-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7347.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004637.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB7A	NM_004637.6	MANE Select	c.482A>C	p.Asn161Thr	missense	Exon 5 of 6	NP_004628.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB7A	ENST00000265062.8	TSL:1 MANE Select	c.482A>C	p.Asn161Thr	missense	Exon 5 of 6	ENSP00000265062.3	P51149
	RAB7A	ENST00000482525.5	TSL:1	c.341A>C	p.Asn114Thr	missense	Exon 5 of 6	ENSP00000417668.1	C9J8S3
	RAB7A	ENST00000901020.1		c.581A>C	p.Asn194Thr	missense	Exon 6 of 7	ENSP00000571079.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease type 2B (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.79	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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909080; hg19: chr3-128526468;