3-128795218-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004637.6(RAB7A):c.-8-142T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 745,182 control chromosomes in the GnomAD database, including 1,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (230 hom., cov: 31)
  • Exomes 𝑓: 0.051 (1006 hom.)
• Consequence: RAB7A NM_004637.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.58

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 3-128795218-T-G is Benign according to our data. Variant chr3-128795218-T-G is described in ClinVar as [Benign]. Clinvar id is 674517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB7A	NM_004637.6	c.-8-142T>G		intron_variant		ENST00000265062.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB7A	ENST00000265062.8	c.-8-142T>G		intron_variant		1	NM_004637.6	P1

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8119 AN: 152114 Hom.: 230 Cov.: 31

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0630

GnomAD4 exome AF: 0.0508 AC: 30132 AN: 592950 Hom.: 1006 Cov.: 7 AF XY: 0.0482 AC XY: 15408 AN XY: 319746

Gnomad4 AFR exome AF: 0.0507

Gnomad4 AMR exome AF: 0.0479

Gnomad4 ASJ exome AF: 0.0912

Gnomad4 EAS exome AF: 0.000122

Gnomad4 SAS exome AF: 0.00748

Gnomad4 FIN exome AF: 0.0578

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0580

GnomAD4 genome AF: 0.0535 AC: 8137 AN: 152232 Hom.: 230 Cov.: 31 AF XY: 0.0527 AC XY: 3923 AN XY: 74442

Gnomad4 AFR AF: 0.0503

Gnomad4 AMR AF: 0.0567

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0645

Gnomad4 NFE AF: 0.0583

Gnomad4 OTH AF: 0.0657

Alfa AF: 0.0581 Hom.: 73

Bravo AF: 0.0549

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.97
Dann	Benign	0.16

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: rs73198858; hg19: chr3-128514061; COSMIC: COSV54042131; COSMIC: COSV54042131;