13-110561374-T-C

Position:

• chr13-110561374-T-C

Variant summary

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

The NM_017817.3(RAB20):​c.146A>G​(p.Tyr49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAB20 NM_017817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

Genes affected

RAB20 (HGNC:18260): (RAB20, member RAS oncogene family) Predicted to enable GTPase activity. Involved in phagosome acidification and phagosome-lysosome fusion. Located in Golgi apparatus and phagocytic vesicle. [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	Protein	UniProt
RAB20	NM_017817.3	c.146A>G	p.Tyr49Cys	missense_variant	1/2	ENST00000267328.5	NP_060287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB20	ENST00000267328.5	c.146A>G	p.Tyr49Cys	missense_variant	1/2	1	NM_017817.3	ENSP00000267328.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456262 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724492

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Nov 26, 2024

The c.146A>G (p.Y49C) alteration is located in exon 1 (coding exon 1) of the RAB20 gene. This alteration results from a A to G substitution at nucleotide position 146, causing the tyrosine (Y) at amino acid position 49 to be replaced by a cysteine (C). 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	0.076
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.53	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.46		Gain of catalytic residue at R47 (P = 0);
MVP		0.70
MPC		1.4
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.75
gMVP		0.77

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: rs1040493667; hg19: chr13-111213721;