7-140425905-A-G

Variant names:

• chr7-140425905-A-G
• rs1274483320
• NM_001008749.3:c.409A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008749.3(RAB19):​c.409A>G​(p.Lys137Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB19 NM_001008749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.734

Genes affected

RAB19 (HGNC:19982): (RAB19, member RAS oncogene family) Predicted to enable GTPase activity. Predicted to be involved in autophagosome assembly and intracellular protein transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09028751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB19	NM_001008749.3	c.409A>G	p.Lys137Glu	missense_variant	Exon 4 of 4	ENST00000537763.6	NP_001008749.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB19	ENST00000537763.6	c.409A>G	p.Lys137Glu	missense_variant	Exon 4 of 4	2	NM_001008749.3	ENSP00000440167.1
RAB19	ENST00000356407.3	c.409A>G	p.Lys137Glu	missense_variant	Exon 3 of 3	1		ENSP00000348778.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409A>G (p.K137E) alteration is located in exon 4 (coding exon 3) of the RAB19 gene. This alteration results from a A to G substitution at nucleotide position 409, causing the lysine (K) at amino acid position 137 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.10	.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.58	.;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.097, 0.11
MutPred		0.45		Loss of ubiquitination at K137 (P = 0.0118);Loss of ubiquitination at K137 (P = 0.0118);Loss of ubiquitination at K137 (P = 0.0118);
MVP		0.28
MPC		0.31
ClinPred		0.15	T
GERP RS		0.20
Varity_R		0.11
gMVP		0.48

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: rs1274483320; hg19: chr7-140125705;