chr3-19976104-A-G

Position:

• chr3-19976104-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004162.5(RAB5A):​c.373A>G​(p.Asn125Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAB5A NM_004162.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

Genes affected

RAB5A (HGNC:9783): (RAB5A, member RAS oncogene family) Enables GDP binding activity; GTP binding activity; and GTPase activity. Involved in several processes, including amyloid-beta clearance by transcytosis; early endosome to late endosome transport; and regulation of exocytosis. Located in several cellular components, including cytoplasmic side of early endosome membrane; nucleoplasm; and terminal bouton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB5A	NM_004162.5	c.373A>G	p.Asn125Asp	missense_variant	4/6	ENST00000273047.9
RAB5A	NM_001292048.2	c.331A>G	p.Asn111Asp	missense_variant	4/6
RAB5A	XM_047448648.1	c.112A>G	p.Asn38Asp	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB5A	ENST00000273047.9	c.373A>G	p.Asn125Asp	missense_variant	4/6	1	NM_004162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461134 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.373A>G (p.N125D) alteration is located in exon 4 (coding exon 3) of the RAB5A gene. This alteration results from a A to G substitution at nucleotide position 373, causing the asparagine (N) at amino acid position 125 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-0.070
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.57	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.27
Sift	Benign	0.31	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;.
Vest4		0.71
MutPred		0.54		Loss of MoRF binding (P = 0.0515);.;
MVP		0.75
MPC		0.54
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.54

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: rs1383291378; hg19: chr3-20017596;