NM_170604.3:c.1528C>T

Variant names:

• chr19-38412938-G-A
• rs181501556
• NM_170604.3:c.1528C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_170604.3(RASGRP4):​c.1528C>T​(p.Arg510Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.212
• Publications: 5 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026447892).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP4	NM_170604.3	MANE Select	c.1528C>T	p.Arg510Cys	missense	Exon 12 of 17	NP_733749.1	Q8TDF6-1
	RASGRP4	NM_001146202.2		c.1486C>T	p.Arg496Cys	missense	Exon 12 of 17	NP_001139674.1	Q8TDF6-2
	RASGRP4	NM_001146205.2		c.1426C>T	p.Arg476Cys	missense	Exon 12 of 17	NP_001139677.1	Q8TDF6-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP4	ENST00000615439.5	TSL:1 MANE Select	c.1528C>T	p.Arg510Cys	missense	Exon 12 of 17	ENSP00000479844.1	Q8TDF6-1
	RASGRP4	ENST00000587738.2	TSL:5	c.1528C>T	p.Arg510Cys	missense	Exon 12 of 17	ENSP00000465772.1	Q8TDF6-1
	RASGRP4	ENST00000586305.5	TSL:1	c.1486C>T	p.Arg496Cys	missense	Exon 12 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 249238 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461336 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000693 AC: 31 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111522

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74504

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.21
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.070
Sift	Benign	0.17	T
Sift4G	Uncertain	0.060	T
Polyphen		0.0020	B
Vest4		0.18
MVP		0.23
MPC		0.38
ClinPred		0.092	T
GERP RS		-4.0
Varity_R		0.11
gMVP		0.46
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs181501556; hg19: chr19-38903578; COSMIC: COSV99385135; COSMIC: COSV99385135;