5-81080117-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_006909.3(RASGRF2):c.888-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,592,060 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (9 hom.)
• Consequence: RASGRF2 NM_006909.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006349
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-81080117-A-G is Benign according to our data. Variant chr5-81080117-A-G is described in ClinVar as [Benign]. Clinvar id is 787037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00514 (783/152244) while in subpopulation AFR AF= 0.0181 (752/41536). AF 95% confidence interval is 0.017. There are 9 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 782 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRF2	NM_006909.3	c.888-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000265080.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRF2	ENST00000265080.9	c.888-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006909.3	P1
RASGRF2	ENST00000503795.1	c.888-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
RASGRF2	ENST00000638442.1	c.888-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
RASGRF2	ENST00000502677.1	n.813-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152126 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00144 AC: 328 AN: 228496 Hom.: 2 AF XY: 0.00110 AC XY: 136 AN XY: 123998

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000397

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000538

GnomAD4 exome AF: 0.000511 AC: 736 AN: 1439816 Hom.: 9 Cov.: 31 AF XY: 0.000458 AC XY: 328 AN XY: 715894

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00514 AC: 783 AN: 152244 Hom.: 9 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74450

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.00616

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.1
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.014
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: rs142461763; hg19: chr5-80375936;