chr19-38414853-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_170604.3(RASGRP4):​c.1225C>T​(p.Leu409Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

RASGRP4
NM_170604.3 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.97
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGRP4NM_170604.3 linkc.1225C>T p.Leu409Phe missense_variant Exon 9 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.1225C>T p.Leu409Phe missense_variant Exon 9 of 17 1 NM_170604.3 ENSP00000479844.1 Q8TDF6-1
RASGRP4ENST00000587738.2 linkc.1225C>T p.Leu409Phe missense_variant Exon 9 of 17 5 ENSP00000465772.1 Q8TDF6-1
RASGRP4ENST00000586305.5 linkc.1183C>T p.Leu395Phe missense_variant Exon 9 of 17 1 ENSP00000467604.1 Q8TDF6-2
RASGRP4ENST00000454404.6 linkc.1123C>T p.Leu375Phe missense_variant Exon 9 of 17 1 ENSP00000416463.2 Q8TDF6-8
RASGRP4ENST00000587753.5 linkc.1018C>T p.Leu340Phe missense_variant Exon 9 of 17 1 ENSP00000468483.1 Q8TDF6-9
RASGRP4ENST00000617966.4 linkc.934C>T p.Leu312Phe missense_variant Exon 7 of 15 5 ENSP00000479888.1 Q8TDF6-7
RASGRP4ENST00000614135.4 linkc.955-1379C>T intron_variant Intron 8 of 15 5 ENSP00000479078.1 Q8TDF6-5
RASGRP4ENST00000622174.4 linkc.664-1379C>T intron_variant Intron 6 of 13 5 ENSP00000484345.1 Q8TDF6-6
RASGRP4ENST00000589358.5 linkn.1225C>T non_coding_transcript_exon_variant Exon 9 of 18 5 ENSP00000465742.1 Q8TDF6-1
RASGRP4ENST00000589474.5 linkn.1183C>T non_coding_transcript_exon_variant Exon 9 of 18 5 ENSP00000466928.1 Q8TDF6-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1225C>T (p.L409F) alteration is located in exon 9 (coding exon 9) of the RASGRP4 gene. This alteration results from a C to T substitution at nucleotide position 1225, causing the leucine (L) at amino acid position 409 to be replaced by a phenylalanine (F). 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
Pathogenic
0.65
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;.;.;.;T;.;T;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;D;D;.;D;D;D;.
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.23
D
MutationAssessor
Uncertain
2.4
.;.;.;.;.;.;M;M
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.7
.;.;.;.;.;D;.;.
REVEL
Uncertain
0.52
Sift
Uncertain
0.0010
.;.;.;.;.;D;.;.
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.;D;D
Vest4
0.79
MutPred
0.67
.;.;.;.;Loss of stability (P = 0.0468);.;Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);
MVP
0.76
MPC
1.0
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.59
gMVP
0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38905493; API