19-38413462-G-A

Variant names:

• chr19-38413462-G-A
• NM_170604.3:c.1243C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):​c.1243C>T​(p.Leu415Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1243C>T	p.Leu415Phe	missense_variant	Exon 10 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1243C>T	p.Leu415Phe	missense_variant	Exon 10 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1243C>T	p.Leu415Phe	missense_variant	Exon 10 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1201C>T	p.Leu401Phe	missense_variant	Exon 10 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1141C>T	p.Leu381Phe	missense_variant	Exon 10 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1036C>T	p.Leu346Phe	missense_variant	Exon 10 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.967C>T	p.Leu323Phe	missense_variant	Exon 9 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.952C>T	p.Leu318Phe	missense_variant	Exon 8 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.676C>T	p.Leu226Phe	missense_variant	Exon 7 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1243C>T		non_coding_transcript_exon_variant	Exon 10 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1201C>T		non_coding_transcript_exon_variant	Exon 10 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717242

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1243C>T (p.L415F) alteration is located in exon 10 (coding exon 10) of the RASGRP4 gene. This alteration results from a C to T substitution at nucleotide position 1243, causing the leucine (L) at amino acid position 415 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;.;.;.;.;T;.;.;T;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D;.;D;D;D;D;D;.
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;.;M;.;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	.;.;.;.;.;.;.;D;D;.;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.017	.;.;.;.;.;.;.;D;D;.;T;.
Sift4G	Uncertain	0.036	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D
Vest4		0.53
MutPred		0.55		.;.;.;.;.;.;Gain of helix (P = 0.0425);.;.;Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);
MVP		0.81
MPC		1.0
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.43

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: chr19-38904102;