Genetic Variant NM_005739.4:c.1243-125A>G (chr15-38506045-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.297

Publications

10 publications found

Variant links:

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

RASGRP1 links:

LOC105370774 (HGNC:):

LOC105370774 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP1	NM_005739.4 link	c.1243-125A>G		intron_variant	Intron 9 of 16	ENST00000310803.10	NP_005730.2	O95267-1B2RA89

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP1	ENST00000310803.10 link	c.1243-125A>G		intron_variant	Intron 9 of 16	1	NM_005739.4	ENSP00000310244.5		O95267-1

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50100

AN:

152036

Hom.:

9039

Cov.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

5777

11555

17332

23110

28887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1552

3104

4656

6208

7760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.330

AC:

50137

AN:

152154

Hom.:

9048

Cov.:

AF XY:

0.340

AC XY:

25331

AN XY:

74394

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22059

AN:

67990

Other (OTH)

AF:

0.321

AC:

677

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1685

3370

5055

6740

8425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over