Genetic Variant RAB7A:p.Leu73Leu (chr3-128806410-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. L73L) has been classified as Uncertain significance.

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:7

Conservation

PhyloP100: -2.00

Publications

17 publications found

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 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

RAB7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 138863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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.219C>T	p.Leu73Leu	synonymous	Exon 4 of 6	NP_004628.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB7A	ENST00000265062.8	TSL:1 MANE Select	c.219C>T	p.Leu73Leu	synonymous	Exon 4 of 6	ENSP00000265062.3	P51149
RAB7A	ENST00000482525.5	TSL:1	c.219C>T	p.Leu73Leu	synonymous	Exon 4 of 6	ENSP00000417668.1	C9J8S3
RAB7A	ENST00000901020.1		c.318C>T	p.Leu106Leu	synonymous	Exon 5 of 7	ENSP00000571079.1

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

GnomAD2 exomes

AF:

0.0442

AC:

11117

AN:

251360

AF XY:

0.0441

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 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

African (AFR)

AF:

0.00929

AC:

311

AN:

33474

American (AMR)

AF:

0.0416

AC:

1859

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0826

AC:

2158

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39698

South Asian (SAS)

AF:

0.00733

AC:

632

AN:

86258

European-Finnish (FIN)

AF:

0.0577

AC:

3084

AN:

53418

Middle Eastern (MID)

AF:

0.0476

AC:

274

AN:

5760

European-Non Finnish (NFE)

AF:

0.0611

AC:

67879

AN:

1111814

Other (OTH)

AF:

0.0504

AC:

3043

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

3849

7697

11546

15394

19243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2498

4996

7494

9992

12490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0416

AC:

6323

AN:

152150

Hom.:

180

Cov.:

AF XY:

0.0412

AC XY:

3062

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41492

American (AMR)

AF:

0.0495

AC:

757

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.00561

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0647

AC:

684

AN:

10574

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0579

AC:

3937

AN:

68010

Other (OTH)

AF:

0.0549

AC:

116

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

310

620

929

1239

1549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0546

Hom.:

402

Bravo

AF:

0.0403

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0589

EpiControl

AF:

0.0618

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Charcot-Marie-Tooth disease type 2B (2)

Charcot-Marie-Tooth disease (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.1

(source)

DANN

Benign

0.63

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over