19-38415065-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):​c.1013G>A​(p.Arg338His) variant causes a missense change. The variant allele was found at a frequency of 0.0000337 in 1,602,962 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 1 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RASGRP4NM_170604.3 linkuse as main transcriptc.1013G>A p.Arg338His missense_variant 9/17 ENST00000615439.5 NP_733749.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RASGRP4ENST00000615439.5 linkuse as main transcriptc.1013G>A p.Arg338His missense_variant 9/171 NM_170604.3 ENSP00000479844 P1Q8TDF6-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000708
AC:
16
AN:
225920
Hom.:
0
AF XY:
0.0000808
AC XY:
10
AN XY:
123788
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000156
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000598
Gnomad SAS exome
AF:
0.000174
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000496
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000358
AC:
52
AN:
1450754
Hom.:
1
Cov.:
32
AF XY:
0.0000361
AC XY:
26
AN XY:
720690
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000163
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000199
Gnomad4 OTH exome
AF:
0.000134
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000697
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000830
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2024The c.1013G>A (p.R338H) alteration is located in exon 9 (coding exon 9) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1013, causing the arginine (R) at amino acid position 338 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.31
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.076
.;.;.;T;.;T;T
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.71
.;T;.;T;T;T;.
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.63
D;D;D;D;D;D;D
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.3
.;.;.;.;.;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.7
.;D;.;.;D;.;.
REVEL
Benign
0.27
Sift
Pathogenic
0.0
.;D;.;.;D;.;.
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;D;D
Vest4
0.57
MVP
0.48
MPC
1.1
ClinPred
0.80
D
GERP RS
4.6
Varity_R
0.74
gMVP
0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763988472; hg19: chr19-38905705; API