5-142875114-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001135608.3(ARHGAP26):c.255A>G(p.Arg85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,612,584 control chromosomes in the GnomAD database, including 126,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (21666 hom., cov: 32)
  • Exomes 𝑓: 0.35 (105148 hom.)
• Consequence: ARHGAP26 NM_001135608.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26

Genes affected

ARHGAP26 (HGNC:17073): (Rho GTPase activating protein 26) Interaction of a cell with the extracellular matrix triggers integrin cell surface receptors to begin signaling cascades that regulate the organization of the actin-cytoskeleton. One of the proteins involved in these cascades is focal adhesion kinase. The protein encoded by this gene is a GTPase activating protein that binds to focal adhesion kinase and mediates the activity of the GTP binding proteins RhoA and Cdc42. Defects in this gene are a cause of juvenile myelomonocytic leukemia (JMML). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-142875114-A-G is Benign according to our data. Variant chr5-142875114-A-G is described in ClinVar as [Benign]. Clinvar id is 3059213.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-142875114-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP26	NM_001135608.3	c.255A>G	p.Arg85=	synonymous_variant	3/23	ENST00000645722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.255A>G	p.Arg85=	synonymous_variant	3/23		NM_001135608.3	P1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72872 AN: 151950 Hom.: 21605 Cov.: 32

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.456

GnomAD3 exomes AF: 0.444 AC: 111672 AN: 251336 Hom.: 30144 AF XY: 0.437 AC XY: 59311 AN XY: 135822

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.869

Gnomad SAS exome AF: 0.614

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.350 AC: 511089 AN: 1460516 Hom.: 105148 Cov.: 35 AF XY: 0.356 AC XY: 258411 AN XY: 726606

Gnomad4 AFR exome AF: 0.812

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.859

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.480 AC: 73001 AN: 152068 Hom.: 21666 Cov.: 32 AF XY: 0.484 AC XY: 35931 AN XY: 74294

Gnomad4 AFR AF: 0.795

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.863

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.459

Alfa AF: 0.336 Hom.: 19394

Bravo AF: 0.508

Asia WGS AF: 0.741 AC: 2574 AN: 3478

EpiCase AF: 0.290

EpiControl AF: 0.286

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ARHGAP26-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	10
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs185200; hg19: chr5-142254679; COSMIC: COSV50825777;