rs4567661

Variant names:

• chr15-38493913-A-C
• rs4567661
• NM_005739.4:c.2259+469T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-38493913-A-C
• chr15-38493913-A-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.2259+469T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,118 control chromosomes in the GnomAD database, including 8,823 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 0.34 (8823 hom., cov: 32)
• Consequence: RASGRP1 NM_005739.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 8 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

ENSG00000286786 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.413 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.2259+469T>G		intron	N/A	NP_005730.2	O95267-1
	RASGRP1	NM_001128602.2		c.2154+469T>G		intron	N/A	NP_001122074.1	O95267-2
	RASGRP1	NM_001306086.2		c.1769-3225T>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.2259+469T>G		intron	N/A	ENSP00000310244.5	O95267-1
	RASGRP1	ENST00000450598.6	TSL:1	c.2154+469T>G		intron	N/A	ENSP00000388540.2	O95267-2
	RASGRP1	ENST00000558432.5	TSL:1	c.2115+469T>G		intron	N/A	ENSP00000453583.2	H0YN83

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51220 AN: 152000 Hom.: 8808 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.343

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.337 AC: 51278 AN: 152118 Hom.: 8823 Cov.: 32 AF XY: 0.341 AC XY: 25344 AN XY: 74354

African (AFR) AF: 0.270 AC: 11214 AN: 41494

American (AMR) AF: 0.399 AC: 6102 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1269 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2024 AN: 5170

South Asian (SAS) AF: 0.429 AC: 2066 AN: 4818

European-Finnish (FIN) AF: 0.335 AC: 3543 AN: 10576

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23913 AN: 67974

Other (OTH) AF: 0.347 AC: 733 AN: 2112

Alfa AF: 0.354 Hom.: 16191

Bravo AF: 0.342

Asia WGS AF: 0.399 AC: 1385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.60
PhyloP100		-0.0030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4567661; hg19: chr15-38786114;