3-120689896-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_173825.5(RABL3):c.646-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,609,376 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (31 hom.)
• Consequence: RABL3 NM_173825.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001018
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.316

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-120689896-C-G is Benign according to our data. Variant chr3-120689896-C-G is described in ClinVar as [Benign]. Clinvar id is 3037805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABL3	NM_173825.5	c.646-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000273375.8
RABL3	NM_001363964.1	c.574-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RABL3	NM_001363965.1	c.688-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RABL3	NR_157022.1	n.960-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABL3	ENST00000273375.8	c.646-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_173825.5	P1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 460 AN: 152038 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00323 AC: 810 AN: 250424 Hom.: 12 AF XY: 0.00297 AC XY: 402 AN XY: 135402

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00158 AC: 2309 AN: 1457220 Hom.: 31 Cov.: 28 AF XY: 0.00159 AC XY: 1155 AN XY: 725364

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0284

Gnomad4 NFE exome AF: 0.000613

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152156 Hom.: 4 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74408

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00232 Hom.: 1

Bravo AF: 0.000529

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RABL3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.3
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0020
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: rs200208680; hg19: chr3-120408743;