rs776295355

Variant names:

• chr19-38411347-C-A
• rs776295355
• NM_170604.3:c.1715G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38411347-C-A
• chr19-38411347-C-T
• chr19-38411347-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):​c.1715G>T​(p.Arg572Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,601,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R572Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003972
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.1715G>T	p.Arg572Leu	missense splice_region	Exon 14 of 17	NP_733749.1	Q8TDF6-1
	RASGRP4	NM_001146202.2		c.1673G>T	p.Arg558Leu	missense splice_region	Exon 14 of 17	NP_001139674.1	Q8TDF6-2
	RASGRP4	NM_001146205.2		c.1613G>T	p.Arg538Leu	missense splice_region	Exon 14 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.1715G>T	p.Arg572Leu	missense splice_region	Exon 14 of 17	ENSP00000479844.1	Q8TDF6-1
	RASGRP4	ENST00000587738.2	TSL:5	c.1715G>T	p.Arg572Leu	missense splice_region	Exon 14 of 17	ENSP00000465772.1	Q8TDF6-1
	RASGRP4	ENST00000586305.5	TSL:1	c.1673G>T	p.Arg558Leu	missense splice_region	Exon 14 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000875 AC: 2 AN: 228476 AF XY: 0.00000808

Gnomad AFR exome AF: 0.0000749

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448998 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 719532

African (AFR) AF: 0.0000603 AC: 2 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 42816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 38934

South Asian (SAS) AF: 0.00 AC: 0 AN: 84306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105760

Other (OTH) AF: 0.00 AC: 0 AN: 59918

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.000121 AC: 5 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000166 AC: 2

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	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.054
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.16
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.027	D
Polyphen		0.25	B
Vest4		0.48
MutPred		0.29		Loss of disorder (P = 0.0506)
MVP		0.83
MPC		0.87
ClinPred		0.60	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.46
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.28
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

Other links and lift over

dbSNP: rs776295355; hg19: chr19-38901987;