3-128807566-C-G

Variant names:

• chr3-128807566-C-G
• rs61758751
• NM_004637.6:c.423C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004637.6(RAB7A):​c.423C>G​(p.Ala141Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,614,168 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: RAB7A NM_004637.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.600
• Publications: 3 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-128807566-C-G is Benign according to our data. Variant chr3-128807566-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.6 with no splicing effect.
• BS2: High AC in GnomAd4 at 387 AD gene.

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.423C>G	p.Ala141Ala	synonymous	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.423C>G	p.Ala141Ala	synonymous	Exon 5 of 6	ENSP00000265062.3	P51149
	RAB7A	ENST00000482525.5	TSL:1	c.282C>G	p.Ala94Ala	synonymous	Exon 5 of 6	ENSP00000417668.1	C9J8S3
	RAB7A	ENST00000901020.1		c.522C>G	p.Ala174Ala	synonymous	Exon 6 of 7	ENSP00000571079.1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00287 AC: 722 AN: 251354 AF XY: 0.00304

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00439 AC: 6423 AN: 1461854 Hom.: 26 Cov.: 32 AF XY: 0.00430 AC XY: 3130 AN XY: 727224

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00620 AC: 162 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86254

European-Finnish (FIN) AF: 0.00133 AC: 71 AN: 53418

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5742

European-Non Finnish (NFE) AF: 0.00515 AC: 5731 AN: 1112006

Other (OTH) AF: 0.00422 AC: 255 AN: 60396

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74484

African (AFR) AF: 0.000818 AC: 34 AN: 41564

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00445 AC: 303 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00283 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Charcot-Marie-Tooth disease type 2B (3)
-	-	3	not specified (3)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	RAB7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		0.60
Mutation Taster		=72/28	polymorphism

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: rs61758751; hg19: chr3-128526409;