19-38410048-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.2014G>A​(p.Asp672Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Consequence

RASGRP4
NM_170604.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.496
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06939012).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGRP4NM_170604.3 linkc.2014G>A p.Asp672Asn missense_variant Exon 17 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.2014G>A p.Asp672Asn missense_variant Exon 17 of 17 1 NM_170604.3 ENSP00000479844.1 Q8TDF6-1
RASGRP4ENST00000587738.2 linkc.2014G>A p.Asp672Asn missense_variant Exon 17 of 17 5 ENSP00000465772.1 Q8TDF6-1
RASGRP4ENST00000586305.5 linkc.1972G>A p.Asp658Asn missense_variant Exon 17 of 17 1 ENSP00000467604.1 Q8TDF6-2
RASGRP4ENST00000454404.6 linkc.1912G>A p.Asp638Asn missense_variant Exon 17 of 17 1 ENSP00000416463.2 Q8TDF6-8
RASGRP4ENST00000587753.5 linkc.1807G>A p.Asp603Asn missense_variant Exon 17 of 17 1 ENSP00000468483.1 Q8TDF6-9
RASGRP4ENST00000614135.4 linkc.1738G>A p.Asp580Asn missense_variant Exon 16 of 16 5 ENSP00000479078.1 Q8TDF6-5
RASGRP4ENST00000617966.4 linkc.1723G>A p.Asp575Asn missense_variant Exon 15 of 15 5 ENSP00000479888.1 Q8TDF6-7
RASGRP4ENST00000622174.4 linkc.1447G>A p.Asp483Asn missense_variant Exon 14 of 14 5 ENSP00000484345.1 Q8TDF6-6
RASGRP4ENST00000589358.5 linkn.2014G>A non_coding_transcript_exon_variant Exon 17 of 18 5 ENSP00000465742.1 Q8TDF6-1
RASGRP4ENST00000589474.5 linkn.1972G>A non_coding_transcript_exon_variant Exon 17 of 18 5 ENSP00000466928.1 Q8TDF6-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
29
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000371
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
0.49
DANN
Benign
0.95
DEOGEN2
Benign
0.0055
.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0067
N
LIST_S2
Benign
0.45
.;.;.;T;T;.;T;T;T;T;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.069
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.26
.;.;.;.;.;.;.;.;N;.;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.57
.;.;.;.;.;.;N;N;.;N;.
REVEL
Benign
0.21
Sift
Benign
0.17
.;.;.;.;.;.;T;T;.;T;.
Sift4G
Benign
0.45
T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;.;.;.;.;B;.;B
Vest4
0.073
MVP
0.40
MPC
0.28
ClinPred
0.052
T
GERP RS
-3.2
Varity_R
0.039
gMVP
0.12

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: rs530924409; hg19: chr19-38900688; API