9-131578589-G-A

Variant names:

• chr9-131578589-G-A
• rs3739497
• NM_001377935.1:c.*908C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377935.1(RAPGEF1):​c.*908C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,358 control chromosomes in the GnomAD database, including 6,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6733 hom., cov: 33)
  • Exomes 𝑓: 0.33 (13 hom.)
• Consequence: RAPGEF1 NM_001377935.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.287
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-131578589-G-A is Benign according to our data. Variant chr9-131578589-G-A is described in ClinVar as [Benign]. Clinvar id is 1274200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF1	NM_001377935.1	c.*908C>T		3_prime_UTR_variant	Exon 27 of 27	ENST00000683357.1	NP_001364864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.*908C>T		3_prime_UTR_variant	Exon 27 of 27		NM_001377935.1	ENSP00000508246.1
RAPGEF1	ENST00000372189.7	c.*908C>T		3_prime_UTR_variant	Exon 24 of 24	1		ENSP00000361263.2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41705 AN: 152036 Hom.: 6731 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.332 AC: 67 AN: 202 Hom.: 13 Cov.: 0 AF XY: 0.311 AC XY: 46 AN XY: 148

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.300 AC: 12 AN: 40

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.358 AC: 43 AN: 120

Other (OTH) AF: 0.333 AC: 10 AN: 30

GnomAD4 genome AF: 0.274 AC: 41731 AN: 152156 Hom.: 6733 Cov.: 33 AF XY: 0.275 AC XY: 20427 AN XY: 74378

African (AFR) AF: 0.109 AC: 4540 AN: 41540

American (AMR) AF: 0.229 AC: 3508 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1327 AN: 3470

East Asian (EAS) AF: 0.177 AC: 915 AN: 5172

South Asian (SAS) AF: 0.336 AC: 1618 AN: 4822

European-Finnish (FIN) AF: 0.378 AC: 4003 AN: 10594

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24755 AN: 67948

Other (OTH) AF: 0.288 AC: 605 AN: 2104

Alfa AF: 0.324 Hom.: 23878

Bravo AF: 0.251

Asia WGS AF: 0.260 AC: 901 AN: 3478

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

- -

Feb 25, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28171541) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.95
DANN	Benign	0.48
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3739497; hg19: chr9-134453976;