5-80960771-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_006909.3(RASGRF2):c.33C>G(p.His11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,322 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: RASGRF2 NM_006909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

Genes affected

RASGRF2 (HGNC:9876): (Ras protein specific guanine nucleotide releasing factor 2) RAS GTPases cycle between an inactive GDP-bound state and an active GTP-bound state. This gene encodes a calcium-regulated nucleotide exchange factor activating both RAS and RAS-related protein, RAC1, through the exchange of bound GDP for GTP, thereby, coordinating the signaling of distinct mitogen-activated protein kinase pathways. [provided by RefSeq, Oct 2011]

RASGRF2-AS1 (HGNC:40499): (RASGRF2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RASGRF2
• BP4: Computational evidence support a benign effect (MetaRNN=0.302092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRF2	NM_006909.3	c.33C>G	p.His11Gln	missense_variant	1/27	ENST00000265080.9
RASGRF2-AS1	NR_105015.1	n.127+10G>C		intron_variant, non_coding_transcript_variant
RASGRF2	XM_005248565.2	c.33C>G	p.His11Gln	missense_variant	1/19
RASGRF2	XM_017009683.2	c.33C>G	p.His11Gln	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRF2	ENST00000265080.9	c.33C>G	p.His11Gln	missense_variant	1/27	1	NM_006909.3	P1
RASGRF2	ENST00000503795.1	c.33C>G	p.His11Gln	missense_variant, NMD_transcript_variant	1/28	1
RASGRF2-AS1	ENST00000505694.1	n.127+10G>C		intron_variant, non_coding_transcript_variant		3
RASGRF2	ENST00000638442.1	c.33C>G	p.His11Gln	missense_variant	1/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242444 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456322 Hom.: 1 Cov.: 31 AF XY: 0.00000967 AC XY: 7 AN XY: 723808

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: 0.0000934

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.33C>G (p.H11Q) alteration is located in exon 1 (coding exon 1) of the RASGRF2 gene. This alteration results from a C to G substitution at nucleotide position 33, causing the histidine (H) at amino acid position 11 to be replaced by a glutamine (Q). 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	0.85
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.053	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.69	N;.
REVEL	Benign	0.28
Sift	Benign	0.34	T;.
Sift4G	Benign	0.72	T;.
Polyphen		0.13	B;.
Vest4		0.47
MutPred		0.46		Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);
MVP		0.50
MPC		2.0
ClinPred		0.64	D
GERP RS		3.4
Varity_R		0.23
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs1189225485; hg19: chr5-80256590;