9-131596338-C-T

Variant names:

• chr9-131596338-C-T
• rs35658906
• NM_001377935.1:c.2649G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4 BP6_Very_Strong BP7 BS2

The NM_001377935.1(RAPGEF1):​c.2649G>A​(p.Gly883Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,613,944 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (47 hom.)
• Consequence: RAPGEF1 NM_001377935.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 2 publications found

Genes affected

RAPGEF1 (HGNC:4568): (Rap guanine nucleotide exchange factor 1) This gene encodes a human guanine nucleotide exchange factor. It transduces signals from CRK by binding the SH3 domain of CRK, and activating several members of the Ras family of GTPases. This signaling cascade that may be involved in apoptosis, integrin-mediated signal transduction, and cell transformation. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.184).
• BP6: Variant 9-131596338-C-T is Benign according to our data. Variant chr9-131596338-C-T is described in ClinVar as [Benign]. Clinvar id is 710212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS2: High AC in GnomAd4 at 748 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF1	NM_001377935.1	c.2649G>A	p.Gly883Gly	synonymous_variant	Exon 17 of 27	ENST00000683357.1	NP_001364864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.2649G>A	p.Gly883Gly	synonymous_variant	Exon 17 of 27		NM_001377935.1	ENSP00000508246.1
RAPGEF1	ENST00000372189.7	c.2091G>A	p.Gly697Gly	synonymous_variant	Exon 14 of 24	1		ENSP00000361263.2

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 748 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00716

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00491 AC: 1224 AN: 249254 AF XY: 0.00519

Gnomad AFR exome AF: 0.000903

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.00781

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00695 AC: 10152 AN: 1461692 Hom.: 47 Cov.: 31 AF XY: 0.00691 AC XY: 5021 AN XY: 727126

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00431 AC: 372 AN: 86258

European-Finnish (FIN) AF: 0.00536 AC: 286 AN: 53400

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00811 AC: 9022 AN: 1111856

Other (OTH) AF: 0.00509 AC: 307 AN: 60372

GnomAD4 genome AF: 0.00491 AC: 748 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74430

African (AFR) AF: 0.000987 AC: 41 AN: 41544

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.00716 AC: 76 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00791 AC: 538 AN: 68012

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00672 Hom.: 1

Bravo AF: 0.00433

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.0
DANN	Benign	0.56
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	polymorphism

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: rs35658906; hg19: chr9-134471725;