rs760702740

Variant names:

• chr19-38414979-C-A
• NM_170604.3:c.1099G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38414979-C-A
• chr19-38414979-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170604.3(RASGRP4):​c.1099G>T​(p.Asp367Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31

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]

ACMG classification

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, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1099G>T	p.Asp367Tyr	missense_variant	Exon 9 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1099G>T	p.Asp367Tyr	missense_variant	Exon 9 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1099G>T	p.Asp367Tyr	missense_variant	Exon 9 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1057G>T	p.Asp353Tyr	missense_variant	Exon 9 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.997G>T	p.Asp333Tyr	missense_variant	Exon 9 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000617966.4	c.808G>T	p.Asp270Tyr	missense_variant	Exon 7 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000587753.5	c.955-63G>T		intron_variant	Intron 8 of 16	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.955-1505G>T		intron_variant	Intron 8 of 15	5		ENSP00000479078.1
RASGRP4	ENST00000622174.4	c.664-1505G>T		intron_variant	Intron 6 of 13	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1099G>T		non_coding_transcript_exon_variant	Exon 9 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1057G>T		non_coding_transcript_exon_variant	Exon 9 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461102 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;.;T;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	2.9	.;.;.;.;.;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.4	.;.;.;.;D;.;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;D
Vest4		0.75
MutPred		0.80		.;.;.;Loss of disorder (P = 0.0205);.;Loss of disorder (P = 0.0205);Loss of disorder (P = 0.0205);
MVP		0.48
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38905619;