Genetic Variant RASGRP4:p.Ala401Thr (chr19-38414877-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):c.1201G>A(p.Ala401Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,600,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

Publications

0 publications found

Variant links:

Genes affected

RASGRP4 (HGNC:18958): (RAS guanyl releasing protein 4) The protein encoded by this gene is a member of the Ras guanyl nucleotide-releasing protein (RasGRP) family of Ras guanine nucleotide exchange factors. It contains a Ras exchange motif, a diacylglycerol-binding domain, and two calcium-binding EF hands. This protein was shown to activate H-Ras in a cation-dependent manner in vitro. Expression of this protein in myeloid cell lines was found to be correlated with elevated level of activated RAS protein, and the RAS activation can be greatly enhanced by phorbol ester treatment, which suggested a role of this protein in diacylglycerol regulated cell signaling pathways. Studies of a mast cell leukemia cell line expressing substantial amounts of abnormal transcripts of this gene indicated that this gene may play an important role in the final stages of mast cell development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]

RASGRP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170604.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP4	NM_170604.3	MANE Select	c.1201G>A	p.Ala401Thr	missense	Exon 9 of 17	NP_733749.1	Q8TDF6-1
RASGRP4	NM_001146202.2		c.1159G>A	p.Ala387Thr	missense	Exon 9 of 17	NP_001139674.1	Q8TDF6-2
RASGRP4	NM_001146205.2		c.1099G>A	p.Ala367Thr	missense	Exon 9 of 17	NP_001139677.1	Q8TDF6-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP4	ENST00000615439.5	TSL:1 MANE Select	c.1201G>A	p.Ala401Thr	missense	Exon 9 of 17	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2	TSL:5	c.1201G>A	p.Ala401Thr	missense	Exon 9 of 17	ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5	TSL:1	c.1159G>A	p.Ala387Thr	missense	Exon 9 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000897

AC:

AN:

223074

AF XY:

0.00000823

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000619

Gnomad FIN exome

AF:

0.0000507

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1448438

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33276

American (AMR)

AF:

0.0000237

AC:

AN:

42258

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25778

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39096

South Asian (SAS)

AF:

0.00

AC:

AN:

84190

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1106238

Other (OTH)

AF:

0.0000167

AC:

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000384

AC:

AN:

5204

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

3.9

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.12

Sift

Uncertain

0.014

Sift4G

Uncertain

0.043

Polyphen

0.97

Vest4

0.54

MutPred

0.51

Gain of catalytic residue at A401 (P = 0.0457)

MVP

0.66

MPC

0.77

ClinPred

0.95

GERP RS

5.0

Varity_R

0.34

gMVP

0.51

Mutation Taster

=47/53

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over