19-38413414-G-A

Variant names:

• chr19-38413414-G-A
• NM_170604.3:c.1291C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_170604.3(RASGRP4):​c.1291C>T​(p.Pro431Ser) variant causes a missense change. 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1291C>T	p.Pro431Ser	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.1291C>T	p.Pro431Ser	missense_variant	Exon 10 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1291C>T	p.Pro431Ser	missense_variant	Exon 10 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1249C>T	p.Pro417Ser	missense_variant	Exon 10 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1189C>T	p.Pro397Ser	missense_variant	Exon 10 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1084C>T	p.Pro362Ser	missense_variant	Exon 10 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.1015C>T	p.Pro339Ser	missense_variant	Exon 9 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.1000C>T	p.Pro334Ser	missense_variant	Exon 8 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.724C>T	p.Pro242Ser	missense_variant	Exon 7 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1291C>T		non_coding_transcript_exon_variant	Exon 10 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1249C>T		non_coding_transcript_exon_variant	Exon 10 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455966 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723600

Gnomad4 AFR exome AF: 0.00

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

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1291C>T (p.P431S) 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 1291, causing the proline (P) at amino acid position 431 to be replaced by a serine (S). 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	0.63
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;.;.;.;.;.;T;.;.;T;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;.;.;D;D;.;D;D;D;D;D;.
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;.;.;M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.0	.;.;.;.;D;.;.;D;D;.;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.022	.;.;.;.;D;.;.;D;D;.;D;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;.;.;.;.;.;.;.;.;D;.;D
Vest4		0.80
MutPred		0.43		.;.;.;.;.;.;Gain of phosphorylation at P431 (P = 0.0088);.;.;Gain of phosphorylation at P431 (P = 0.0088);.;Gain of phosphorylation at P431 (P = 0.0088);
MVP		0.76
MPC		0.98
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.84

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: chr19-38904054;