18-8635613-G-T

Position:

• chr18-8635613-G-T

Variant summary

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

The NM_001025300.3(RAB12):​c.795G>T​(p.Gln265His) 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: 33)
• Consequence: RAB12 NM_001025300.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0580

Genes affected

RAB12 (HGNC:31332): (RAB12, member RAS oncogene family) Enables GDP binding activity. Predicted to be involved in several processes, including cellular response to insulin stimulus; endosome to lysosome transport; and secretion by cell. Predicted to act upstream of or within cellular response to interferon-gamma. Predicted to be located in lysosome; phagocytic vesicle; and recycling endosome membrane. Predicted to be active in Golgi apparatus; cytoplasmic vesicle; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000266708 (HGNC:):

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
RAB12	NM_001025300.3	c.795G>T	p.Gln265His	missense_variant	4/6	ENST00000649141.2	NP_001020471.3
RAB12	XM_006722300.4	c.411G>T	p.Gln137His	missense_variant	4/6		XP_006722363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB12	ENST00000649141.2	c.795G>T	p.Gln265His	missense_variant	4/6		NM_001025300.3	ENSP00000497886.1
ENSG00000266708	ENST00000580267.1	n.346C>A		non_coding_transcript_exon_variant	2/2	2
RAB12	ENST00000580987.1	n.*46G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Mar 01, 2023

The c.507G>T (p.Q169H) alteration is located in exon 4 (coding exon 4) of the RAB12 gene. This alteration results from a G to T substitution at nucleotide position 507, causing the glutamine (Q) at amino acid position 169 to be replaced by a histidine (H). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.016	.;D
Sift4G	Uncertain	0.021	.;D
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.32		.;Gain of catalytic residue at R167 (P = 0.0608);
MVP		0.72
MPC		0.75
ClinPred		0.96	D
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-8635611;