15-38530704-T-C

Variant names:

• chr15-38530704-T-C
• rs7403531
• NM_005739.4:c.221-4300A>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.221-4300A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 152,168 control chromosomes in the GnomAD database, including 44,572 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 0.76 (44572 hom., cov: 32)
• Consequence: RASGRP1 NM_005739.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 81 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: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259598 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP1	NM_005739.4	c.221-4300A>G		intron_variant	Intron 2 of 16	ENST00000310803.10	NP_005730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP1	ENST00000310803.10	c.221-4300A>G		intron_variant	Intron 2 of 16	1	NM_005739.4	ENSP00000310244.5

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116082 AN: 152050 Hom.: 44535 Cov.: 32

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.750

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

GnomAD4 genome AF: 0.763 AC: 116171 AN: 152168 Hom.: 44572 Cov.: 32 AF XY: 0.758 AC XY: 56398 AN XY: 74374

African (AFR) AF: 0.807 AC: 33506 AN: 41526

American (AMR) AF: 0.661 AC: 10102 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2587 AN: 3468

East Asian (EAS) AF: 0.634 AC: 3275 AN: 5164

South Asian (SAS) AF: 0.742 AC: 3579 AN: 4824

European-Finnish (FIN) AF: 0.777 AC: 8233 AN: 10592

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.772 AC: 52500 AN: 67996

Other (OTH) AF: 0.751 AC: 1588 AN: 2114

Alfa AF: 0.763 Hom.: 141803

Bravo AF: 0.758

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.2
DANN	Benign	0.67
PhyloP100		0.29
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

Other links and lift over

dbSNP: rs7403531; hg19: chr15-38822905;