chr7-140407691-C-A

Position:

• chr7-140407691-C-A

Variant summary

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

The NM_001008749.3(RAB19):​c.45C>A​(p.Asp15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAB19 NM_001008749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.387

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 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
RAB19	NM_001008749.3	c.45C>A	p.Asp15Glu	missense_variant	2/4	ENST00000537763.6	NP_001008749.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB19	ENST00000537763.6	c.45C>A	p.Asp15Glu	missense_variant	2/4	2	NM_001008749.3	ENSP00000440167.1
RAB19	ENST00000356407.3	c.45C>A	p.Asp15Glu	missense_variant	1/3	1		ENSP00000348778.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Dec 21, 2023

The c.45C>A (p.D15E) alteration is located in exon 2 (coding exon 1) of the RAB19 gene. This alteration results from a C to A substitution at nucleotide position 45, causing the aspartic acid (D) at amino acid position 15 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;.
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.3	.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.98	.;D;D
Vest4		0.84, 0.90
MutPred		0.61		Loss of ubiquitination at K19 (P = 0.1441);Loss of ubiquitination at K19 (P = 0.1441);Loss of ubiquitination at K19 (P = 0.1441);
MVP		0.53
MPC		0.79
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.77
gMVP		0.63

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: rs1434754327; hg19: chr7-140107491;