3-120709774-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173825.5(RABL3):c.268+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,598,902 control chromosomes in the GnomAD database, including 79,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6272 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73436 hom.)
• Consequence: RABL3 NM_173825.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001029
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0730

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-120709774-T-C is Benign according to our data. Variant chr3-120709774-T-C is described in ClinVar as [Benign]. Clinvar id is 3059517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RABL3	NM_173825.5	c.268+6A>G		splice_donor_region_variant, intron_variant		ENST00000273375.8
RABL3	NM_001363964.1	c.268+6A>G		splice_donor_region_variant, intron_variant
RABL3	NM_001363965.1	c.268+6A>G		splice_donor_region_variant, intron_variant
RABL3	NR_157022.1	n.582+6A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RABL3	ENST00000273375.8	c.268+6A>G		splice_donor_region_variant, intron_variant		1	NM_173825.5	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41899 AN: 151724 Hom.: 6266 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.276 AC: 67139 AN: 243558 Hom.: 10319 AF XY: 0.276 AC XY: 36344 AN XY: 131768

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.311 AC: 450282 AN: 1447060 Hom.: 73436 Cov.: 28 AF XY: 0.306 AC XY: 220744 AN XY: 720334

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.410

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.276 AC: 41929 AN: 151842 Hom.: 6272 Cov.: 32 AF XY: 0.279 AC XY: 20685 AN XY: 74204

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.261

Alfa AF: 0.318 Hom.: 7675

Bravo AF: 0.259

Asia WGS AF: 0.168 AC: 585 AN: 3478

EpiCase AF: 0.322

EpiControl AF: 0.321

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

Nov 05, 2019

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	-0.84
Cadd	Benign	6.1
Dann	Benign	0.68

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: rs11720353; hg19: chr3-120428621;