chr3-128806410-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004637.6(RAB7A):c.219C>T(p.Leu73Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,613,822 control chromosomes in the GnomAD database, including 2,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 180 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2491 hom. )

Consequence

RAB7A
NM_004637.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.00

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 3-128806410-C-T is Benign according to our data. Variant chr3-128806410-C-T is described in ClinVar as [Benign]. Clinvar id is 138863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128806410-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB7A	NM_004637.6 link	c.219C>T	p.Leu73Leu	synonymous_variant	Exon 4 of 6	ENST00000265062.8	NP_004628.4	P51149A0A158RFU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB7A	ENST00000265062.8 link	c.219C>T	p.Leu73Leu	synonymous_variant	Exon 4 of 6	1	NM_004637.6	ENSP00000265062.3		P51149

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6312

AN:

152032

Hom.:

179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0496

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00540

Gnomad FIN

AF:

0.0647

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0578

Gnomad OTH

AF:

0.0522

GnomAD3 exomes

AF:

0.0442

AC:

11117

AN:

251360

Hom.:

349

AF XY:

0.0441

AC XY:

5996

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.0412

Gnomad ASJ exome

AF:

0.0809

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00653

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0612

Gnomad OTH exome

AF:

0.0543

GnomAD4 exome

AF:

0.0542

AC:

79265

AN:

1461672

Hom.:

2491

Cov.:

AF XY:

0.0531

AC XY:

38576

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00929

Gnomad4 AMR exome

AF:

0.0416

Gnomad4 ASJ exome

AF:

0.0826

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.00733

Gnomad4 FIN exome

AF:

0.0577

Gnomad4 NFE exome

AF:

0.0611

Gnomad4 OTH exome

AF:

0.0504

GnomAD4 genome

AF:

0.0416

AC:

6323

AN:

152150

Hom.:

180

Cov.:

AF XY:

0.0412

AC XY:

3062

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0110

Gnomad4 AMR

AF:

0.0495

Gnomad4 ASJ

AF:

0.0801

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.00561

Gnomad4 FIN

AF:

0.0647

Gnomad4 NFE

AF:

0.0579

Gnomad4 OTH

AF:

0.0549

Alfa

AF:

0.0560

Hom.:

346

Bravo

AF:

0.0403

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0589

EpiControl

AF:

0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2B

Benign:3

Apr 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 03, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.1

DANN

Benign

0.63

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over