3-120694183-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173825.5(RABL3):c.576T>G(p.Asn192Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RABL3 NM_173825.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

Genes affected

RABL3 (HGNC:18072): (RAB, member of RAS oncogene family like 3) Predicted to enable GTP binding activity; GTPase activity; and protein homodimerization activity. Involved in regulation of Ras protein signal transduction and regulation of protein lipidation. Predicted to be active in endomembrane system. Implicated in pancreatic cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABL3	NM_173825.5	c.576T>G	p.Asn192Lys	missense_variant	6/8	ENST00000273375.8
RABL3	NM_001363965.1	c.576T>G	p.Asn192Lys	missense_variant	6/9
RABL3	NM_001363964.1	c.535-3696T>G		intron_variant
RABL3	NR_157022.1	n.890T>G		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABL3	ENST00000273375.8	c.576T>G	p.Asn192Lys	missense_variant	6/8	1	NM_173825.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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 05, 2021

The c.576T>G (p.N192K) alteration is located in exon 6 (coding exon 6) of the RABL3 gene. This alteration results from a T to G substitution at nucleotide position 576, causing the asparagine (N) at amino acid position 192 to be replaced by a lysine (K). 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	0.93
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.14	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.47		Gain of catalytic residue at N192 (P = 0.0095);
MVP		0.62
MPC		0.68
ClinPred		0.92	D
GERP RS		2.0
Varity_R		0.26
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr3-120413030;