5-142875114-A-G

Variant names:

• chr5-142875114-A-G
• rs185200
• NM_001135608.3:c.255A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001135608.3(ARHGAP26):​c.255A>G​(p.Arg85Arg) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.48 (21666 hom., cov: 32)
  • Exomes 𝑓: 0.35 (105148 hom.)
• Consequence: ARHGAP26 NM_001135608.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.26
• Publications: 19 publications found

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]

ARHGAP26 Gene-Disease associations (from GenCC):

• juvenile myelomonocytic leukemia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 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 no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.255A>G	p.Arg85Arg	synonymous_variant	Exon 3 of 23	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.255A>G	p.Arg85Arg	synonymous_variant	Exon 3 of 23		NM_001135608.3	ENSP00000495131.1

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

GnomAD2 exomes AF: 0.444 AC: 111672 AN: 251336 AF XY: 0.437

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 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

African (AFR) AF: 0.812 AC: 27160 AN: 33450

American (AMR) AF: 0.538 AC: 24038 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8471 AN: 26124

East Asian (EAS) AF: 0.859 AC: 34105 AN: 39688

South Asian (SAS) AF: 0.606 AC: 52230 AN: 86218

European-Finnish (FIN) AF: 0.297 AC: 15859 AN: 53404

Middle Eastern (MID) AF: 0.431 AC: 2476 AN: 5740

European-Non Finnish (NFE) AF: 0.291 AC: 322789 AN: 1110820

Other (OTH) AF: 0.397 AC: 23961 AN: 60358

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

African (AFR) AF: 0.795 AC: 32984 AN: 41506

American (AMR) AF: 0.455 AC: 6954 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3468

East Asian (EAS) AF: 0.863 AC: 4468 AN: 5176

South Asian (SAS) AF: 0.627 AC: 3019 AN: 4816

European-Finnish (FIN) AF: 0.301 AC: 3179 AN: 10548

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19892 AN: 67958

Other (OTH) AF: 0.459 AC: 969 AN: 2112

Alfa AF: 0.359 Hom.: 48467

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: no assertion criteria provided

Submissions by phenotype

ARHGAP26-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		1.3
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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