rs4465567

Variant names:

• chr15-38506045-T-C
• rs4465567
• NM_005739.4:c.1243-125A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005739.4(RASGRP1):​c.1243-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 700,122 control chromosomes in the GnomAD database, including 50,294 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9048 hom., cov: 33)
  • Exomes 𝑓: 0.37 (41246 hom.)
• Consequence: RASGRP1 NM_005739.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297
• Publications: 10 publications found

Genes affected

RASGRP1 (HGNC:9878): (RAS guanyl releasing protein 1) This gene is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor (GEF) domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. It activates the Erk/MAP kinase cascade and regulates T-cells and B-cells development, homeostasis and differentiation. Alternatively spliced transcript variants encoding different isoforms have been identified. Altered expression of the different isoforms of this protein may be a cause of susceptibility to systemic lupus erythematosus (SLE). [provided by RefSeq, Jul 2008]

RASGRP1 Gene-Disease associations (from GenCC):

• immunodeficiency 64

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105370774 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP1	NM_005739.4	MANE Select	c.1243-125A>G		intron	N/A	NP_005730.2	O95267-1
	RASGRP1	NM_001128602.2		c.1243-125A>G		intron	N/A	NP_001122074.1	O95267-2
	RASGRP1	NM_001306086.2		c.1243-125A>G		intron	N/A	NP_001293015.1	O95267-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP1	ENST00000310803.10	TSL:1 MANE Select	c.1243-125A>G		intron	N/A	ENSP00000310244.5	O95267-1
	RASGRP1	ENST00000450598.6	TSL:1	c.1243-125A>G		intron	N/A	ENSP00000388540.2	O95267-2
	RASGRP1	ENST00000558432.5	TSL:1	c.1099-125A>G		intron	N/A	ENSP00000453583.2	H0YN83

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50100 AN: 152036 Hom.: 9039 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.370 AC: 202980 AN: 547968 Hom.: 41246 AF XY: 0.377 AC XY: 108324 AN XY: 287014

African (AFR) AF: 0.227 AC: 3212 AN: 14164

American (AMR) AF: 0.430 AC: 9661 AN: 22464

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 4565 AN: 15398

East Asian (EAS) AF: 0.696 AC: 21744 AN: 31238

South Asian (SAS) AF: 0.529 AC: 25762 AN: 48696

European-Finnish (FIN) AF: 0.409 AC: 15913 AN: 38934

Middle Eastern (MID) AF: 0.376 AC: 1426 AN: 3794

European-Non Finnish (NFE) AF: 0.321 AC: 110426 AN: 344202

Other (OTH) AF: 0.353 AC: 10271 AN: 29078

GnomAD4 genome AF: 0.330 AC: 50137 AN: 152154 Hom.: 9048 Cov.: 33 AF XY: 0.340 AC XY: 25331 AN XY: 74394

African (AFR) AF: 0.225 AC: 9354 AN: 41518

American (AMR) AF: 0.391 AC: 5984 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1091 AN: 3472

East Asian (EAS) AF: 0.692 AC: 3583 AN: 5178

South Asian (SAS) AF: 0.551 AC: 2655 AN: 4820

European-Finnish (FIN) AF: 0.405 AC: 4273 AN: 10560

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22059 AN: 67990

Other (OTH) AF: 0.321 AC: 677 AN: 2108

Alfa AF: 0.324 Hom.: 13573

Bravo AF: 0.322

Asia WGS AF: 0.567 AC: 1967 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4465567;

hg19: chr15-38798246;

COSMIC: COSV60364721;

COSMIC: COSV60364721;