4-81445634-C-T

Variant summary

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

The NM_152545.3(RASGEF1B):c.826-6G>A 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 0.141 in 1,608,228 control chromosomes in the GnomAD database, including 22,120 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 0.22 (5944 hom., cov: 33)
  • Exomes 𝑓: 0.13 (16176 hom.)
• Consequence: RASGEF1B NM_152545.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002679
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.81

Genes affected

RASGEF1B (HGNC:24881): (RasGEF domain family member 1B) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. Predicted to be located in early endosome; late endosome; and midbody. [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=-0.94).
• BP6: Variant 4-81445634-C-T is Benign according to our data. Variant chr4-81445634-C-T is described in ClinVar as [Benign]. Clinvar id is 3059809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGEF1B	NM_152545.3	c.826-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264400.7
RASGEF1B	NM_001300735.2	c.823-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RASGEF1B	NM_001300736.2	c.700-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGEF1B	ENST00000264400.7	c.826-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_152545.3	A1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33572 AN: 151920 Hom.: 5929 Cov.: 33

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0648

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.128 AC: 32227 AN: 250886 Hom.: 3515 AF XY: 0.122 AC XY: 16522 AN XY: 135610

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.0673

Gnomad ASJ exome AF: 0.0611

Gnomad EAS exome AF: 0.0194

Gnomad SAS exome AF: 0.0713

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.133 AC: 193379 AN: 1456190 Hom.: 16176 Cov.: 29 AF XY: 0.129 AC XY: 93747 AN XY: 724770

Gnomad4 AFR exome AF: 0.517

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.0567

Gnomad4 EAS exome AF: 0.0222

Gnomad4 SAS exome AF: 0.0707

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.221 AC: 33618 AN: 152038 Hom.: 5944 Cov.: 33 AF XY: 0.217 AC XY: 16101 AN XY: 74320

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0619

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0643

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.181

Alfa AF: 0.146 Hom.: 1137

Bravo AF: 0.229

Asia WGS AF: 0.0810 AC: 280 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASGEF1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 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	-0.94
Cadd	Benign	0.0020
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.024
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: rs28560455; hg19: chr4-82366788; COSMIC: COSV52337466;