19-38415065-C-T
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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
NM_170604.3 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 3.99
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]
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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 |
---|---|---|---|---|---|---|---|---|
RASGRP4 | NM_170604.3 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
RASGRP4 | ENST00000615439.5 | c.1013G>A | p.Arg338His | missense_variant | 9/17 | 1 | NM_170604.3 | ENSP00000479844 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000708 AC: 16AN: 225920Hom.: 0 AF XY: 0.0000808 AC XY: 10AN XY: 123788
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GnomAD4 exome AF: 0.0000358 AC: 52AN: 1450754Hom.: 1 Cov.: 32 AF XY: 0.0000361 AC XY: 26AN XY: 720690
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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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 submitter | clinical testing | Ambry Genetics | Jan 23, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;.;.;T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.;T;T;T;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;.;.;M;M
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;D;.;.
REVEL
Benign
Sift
Pathogenic
.;D;.;.;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;.;.;.;.;D;D
Vest4
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at