19-38422124-A-G

Variant names:

• chr19-38422124-A-G
• rs892055
• NM_170604.3:c.53T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 42 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.53T>C		non_coding_transcript_exon_variant	Exon 2 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.53T>C		non_coding_transcript_exon_variant	Exon 2 of 18	5		ENSP00000466928.1

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

GnomAD2 exomes AF: 0.429 AC: 105128 AN: 245178 AF XY: 0.427

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 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

African (AFR) AF: 0.596 AC: 19896 AN: 33402

American (AMR) AF: 0.470 AC: 20980 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10298 AN: 26070

East Asian (EAS) AF: 0.520 AC: 20564 AN: 39548

South Asian (SAS) AF: 0.564 AC: 48561 AN: 86142

European-Finnish (FIN) AF: 0.401 AC: 20910 AN: 52194

Middle Eastern (MID) AF: 0.352 AC: 2026 AN: 5760

European-Non Finnish (NFE) AF: 0.349 AC: 387260 AN: 1110802

Other (OTH) AF: 0.394 AC: 23727 AN: 60276

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

African (AFR) AF: 0.593 AC: 24577 AN: 41448

American (AMR) AF: 0.415 AC: 6342 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1322 AN: 3466

East Asian (EAS) AF: 0.554 AC: 2854 AN: 5156

South Asian (SAS) AF: 0.583 AC: 2815 AN: 4828

European-Finnish (FIN) AF: 0.405 AC: 4265 AN: 10538

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23522 AN: 67868

Other (OTH) AF: 0.415 AC: 873 AN: 2106

Alfa AF: 0.379 Hom.: 55841

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
PhyloP100		2.8
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
Mutation Taster		=100/0	polymorphism (auto)

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: rs892055; hg19: chr19-38912764; COSMIC: COSV107352715; COSMIC: COSV107352715;