Genetic Variant RASGRP4:p.Asn497Ile (chr19-38412976-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):c.1490A>T(p.Asn497Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N497S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

1 publications found

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]

RASGRP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170604.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP4	NM_170604.3	MANE Select	c.1490A>T	p.Asn497Ile	missense	Exon 12 of 17	NP_733749.1	Q8TDF6-1
RASGRP4	NM_001146202.2		c.1448A>T	p.Asn483Ile	missense	Exon 12 of 17	NP_001139674.1	Q8TDF6-2
RASGRP4	NM_001146205.2		c.1388A>T	p.Asn463Ile	missense	Exon 12 of 17	NP_001139677.1	Q8TDF6-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP4	ENST00000615439.5	TSL:1 MANE Select	c.1490A>T	p.Asn497Ile	missense	Exon 12 of 17	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2	TSL:5	c.1490A>T	p.Asn497Ile	missense	Exon 12 of 17	ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5	TSL:1	c.1448A>T	p.Asn483Ile	missense	Exon 12 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.0031

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

0.16

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.8

PhyloP100

1.5

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.9

REVEL

Benign

0.19

Sift

Benign

0.036

Sift4G

Uncertain

0.0020

Polyphen

0.97

Vest4

0.70

MutPred

0.53

Loss of catalytic residue at N497 (P = 0.002)

MVP

0.59

MPC

0.94

ClinPred

0.97

GERP RS

1.7

Varity_R

0.36

gMVP

0.65

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over