4-81434650-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152545.3(RASGEF1B):c.1189G>A(p.Val397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,590,554 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (171 hom.)
• Consequence: RASGEF1B NM_152545.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.832

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 (MetaRNN=0.0090741515).
• BP6: Variant 4-81434650-C-T is Benign according to our data. Variant chr4-81434650-C-T is described in ClinVar as [Benign]. Clinvar id is 3041994.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0136 (19499/1438312) while in subpopulation MID AF= 0.0195 (112/5732). AF 95% confidence interval is 0.0166. There are 171 homozygotes in gnomad4_exome. There are 9382 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGEF1B	NM_152545.3	c.1189G>A	p.Val397Ile	missense_variant	11/14	ENST00000264400.7
RASGEF1B	NM_001300735.2	c.1186G>A	p.Val396Ile	missense_variant	11/14
RASGEF1B	NM_001300736.2	c.1063G>A	p.Val355Ile	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGEF1B	ENST00000264400.7	c.1189G>A	p.Val397Ile	missense_variant	11/14	2	NM_152545.3	A1

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1476 AN: 152124 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00942 AC: 2367 AN: 251142 Hom.: 21 AF XY: 0.00936 AC XY: 1271 AN XY: 135720

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0136 AC: 19499 AN: 1438312 Hom.: 171 Cov.: 27 AF XY: 0.0131 AC XY: 9382 AN XY: 717148

Gnomad4 AFR exome AF: 0.00297

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00968 AC: 1474 AN: 152242 Hom.: 13 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74430

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0142 Hom.: 30

Bravo AF: 0.0108

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0152 AC: 131

ExAC AF: 0.00916 AC: 1112

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0162

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

Feb 14, 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	20
Dann	Benign	0.29
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.30	N;N;.;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.0	B;B;.;B
Vest4		0.19
MVP		0.18
MPC		0.24
ClinPred		0.0083	T
GERP RS		3.7
Varity_R		0.057
gMVP		0.093

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

LitVar

Other links and lift over

dbSNP: rs34211143; hg19: chr4-82355804; COSMIC: COSV105089253; COSMIC: COSV105089253;