15-38546063-T-C

Variant names:

• chr15-38546063-T-C
• rs8035957
• NM_005739.4:c.220+13758A>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.220+13758A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,984 control chromosomes in the GnomAD database, including 14,999 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 0.41 (14999 hom., cov: 32)
• Consequence: RASGRP1 NM_005739.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 38 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 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.220+13758A>G		intron	N/A	NP_005730.2	O95267-1
	RASGRP1	NM_001128602.2		c.220+13758A>G		intron	N/A	NP_001122074.1	O95267-2
	RASGRP1	NM_001306086.2		c.220+13758A>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.220+13758A>G		intron	N/A	ENSP00000310244.5	O95267-1
	RASGRP1	ENST00000450598.6	TSL:1	c.220+13758A>G		intron	N/A	ENSP00000388540.2	O95267-2
	RASGRP1	ENST00000558432.5	TSL:1	c.76+13758A>G		intron	N/A	ENSP00000453583.2	H0YN83

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61863 AN: 151868 Hom.: 14964 Cov.: 32

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.408 AC: 61955 AN: 151984 Hom.: 14999 Cov.: 32 AF XY: 0.408 AC XY: 30314 AN XY: 74288

African (AFR) AF: 0.667 AC: 27610 AN: 41396

American (AMR) AF: 0.411 AC: 6282 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3472

East Asian (EAS) AF: 0.590 AC: 3057 AN: 5180

South Asian (SAS) AF: 0.368 AC: 1769 AN: 4810

European-Finnish (FIN) AF: 0.292 AC: 3080 AN: 10558

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.264 AC: 17958 AN: 67986

Other (OTH) AF: 0.379 AC: 801 AN: 2114

Alfa AF: 0.322 Hom.: 29943

Bravo AF: 0.426

Asia WGS AF: 0.477 AC: 1659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.079
DANN	Benign	0.34
PhyloP100		-1.5
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: rs8035957;

hg19: chr15-38838264;