rs892055

Positions:

• chr19-38422124-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_170604.3(RASGRP4):​c.53T>C​(p.Ile18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,610,698 control chromosomes in the GnomAD database, including 125,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.44 (15742 hom., cov: 33)
  • Exomes 𝑓: 0.38 (109572 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9170338E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.53T>C	p.Ile18Thr	missense_variant	2/17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.53T>C	p.Ile18Thr	missense_variant	2/17	1	NM_170604.3	ENSP00000479844	P1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66712 AN: 151776 Hom.: 15694 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.429 AC: 105128 AN: 245178 Hom.: 23808 AF XY: 0.427 AC XY: 56966 AN XY: 133304

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.552

Gnomad SAS exome AF: 0.574

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.380 AC: 554222 AN: 1458804 Hom.: 109572 Cov.: 38 AF XY: 0.384 AC XY: 278649 AN XY: 725706

Gnomad4 AFR exome AF: 0.596

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.520

Gnomad4 SAS exome AF: 0.564

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.440 AC: 66826 AN: 151894 Hom.: 15742 Cov.: 33 AF XY: 0.447 AC XY: 33218 AN XY: 74240

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.415

Alfa AF: 0.367 Hom.: 27279

Bravo AF: 0.446

TwinsUK AF: 0.357 AC: 1323

ALSPAC AF: 0.362 AC: 1395

ESP6500AA AF: 0.579 AC: 2221

ESP6500EA AF: 0.353 AC: 2908

ExAC AF: 0.426 AC: 51503

Asia WGS AF: 0.616 AC: 2139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.15
DEOGEN2	Benign	0.0029	.;.;.;.;.;.;T;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00083	N
LIST_S2	Benign	0.16	.;.;.;T;T;.;T;T;T;T;T;.
MetaRNN	Benign	0.000019	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.6	N;N;N;N;N;N;.;N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.63	.;.;.;.;N;.;.;N;N;.;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	.;.;.;.;T;.;.;T;T;.;T;.
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;.;B;.;B
Vest4		0.0070
MPC		0.35
ClinPred		0.0034	T
GERP RS		4.1
Varity_R		0.031
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs892055; hg19: chr19-38912764;