19-38411172-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170604.3(RASGRP4):​c.1795G>A​(p.Asp599Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.862
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12161088).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGRP4NM_170604.3 linkc.1795G>A p.Asp599Asn missense_variant Exon 15 of 17 ENST00000615439.5 NP_733749.1 Q8TDF6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASGRP4ENST00000615439.5 linkc.1795G>A p.Asp599Asn missense_variant Exon 15 of 17 1 NM_170604.3 ENSP00000479844.1 Q8TDF6-1
RASGRP4ENST00000587738.2 linkc.1795G>A p.Asp599Asn missense_variant Exon 15 of 17 5 ENSP00000465772.1 Q8TDF6-1
RASGRP4ENST00000586305.5 linkc.1753G>A p.Asp585Asn missense_variant Exon 15 of 17 1 ENSP00000467604.1 Q8TDF6-2
RASGRP4ENST00000454404.6 linkc.1693G>A p.Asp565Asn missense_variant Exon 15 of 17 1 ENSP00000416463.2 Q8TDF6-8
RASGRP4ENST00000587753.5 linkc.1588G>A p.Asp530Asn missense_variant Exon 15 of 17 1 ENSP00000468483.1 Q8TDF6-9
RASGRP4ENST00000614135.4 linkc.1519G>A p.Asp507Asn missense_variant Exon 14 of 16 5 ENSP00000479078.1 Q8TDF6-5
RASGRP4ENST00000617966.4 linkc.1504G>A p.Asp502Asn missense_variant Exon 13 of 15 5 ENSP00000479888.1 Q8TDF6-7
RASGRP4ENST00000622174.4 linkc.1228G>A p.Asp410Asn missense_variant Exon 12 of 14 5 ENSP00000484345.1 Q8TDF6-6
RASGRP4ENST00000589358.5 linkn.1795G>A non_coding_transcript_exon_variant Exon 15 of 18 5 ENSP00000465742.1 Q8TDF6-1
RASGRP4ENST00000589474.5 linkn.1753G>A non_coding_transcript_exon_variant Exon 15 of 18 5 ENSP00000466928.1 Q8TDF6-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000362
AC:
9
AN:
248922
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135112
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.0000996
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000620
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000369
AC:
54
AN:
1461590
Hom.:
0
Cov.:
32
AF XY:
0.0000454
AC XY:
33
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000309
Hom.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000496
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 15, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1795G>A (p.D599N) alteration is located in exon 15 (coding exon 15) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1795, causing the aspartic acid (D) at amino acid position 599 to be replaced by an asparagine (N). 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
0.079
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0074
.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.74
.;.;.;T;T;.;T;T;T;T;.
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.0
.;.;.;.;.;.;.;.;L;.;L
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.1
.;.;.;.;.;.;N;N;.;N;.
REVEL
Benign
0.16
Sift
Benign
0.33
.;.;.;.;.;.;T;T;.;T;.
Sift4G
Benign
0.50
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.97
D;.;.;.;.;.;.;.;B;.;B
Vest4
0.33
MVP
0.71
MPC
0.50
ClinPred
0.26
T
GERP RS
5.1
Varity_R
0.081
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs142842646; hg19: chr19-38901812; COSMIC: COSV99385092; COSMIC: COSV99385092; API