5-142771377-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001135608.3(ARHGAP26):c.154+462T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,231,858 control chromosomes in the GnomAD database, including 28,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (13941 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14924 hom.)
• Consequence: ARHGAP26 NM_001135608.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00700

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-142771377-T-C is Benign according to our data. Variant chr5-142771377-T-C is described in ClinVar as [Benign]. Clinvar id is 3055505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP26	NM_001135608.3	c.154+462T>C		intron_variant		ENST00000645722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.154+462T>C		intron_variant			NM_001135608.3	P1
ARHGAP26	ENST00000274498.9	c.154+462T>C		intron_variant		1
ARHGAP26	ENST00000642734.1	c.46+2T>C		splice_donor_variant

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47692 AN: 151920 Hom.: 13892 Cov.: 33

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.0912

Gnomad OTH AF: 0.284

GnomAD4 exome AF: 0.118 AC: 127768 AN: 1079820 Hom.: 14924 Cov.: 31 AF XY: 0.117 AC XY: 59396 AN XY: 509798

Gnomad4 AFR exome AF: 0.804

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0871

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.314 AC: 47792 AN: 152038 Hom.: 13941 Cov.: 33 AF XY: 0.313 AC XY: 23282 AN XY: 74314

Gnomad4 AFR AF: 0.770

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.0912

Gnomad4 OTH AF: 0.284

Alfa AF: 0.210 Hom.: 1033

Bravo AF: 0.348

TwinsUK AF: 0.0914 AC: 339

ALSPAC AF: 0.0934 AC: 360

Asia WGS AF: 0.347 AC: 1207 AN: 3478

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

May 10, 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	-0.87
Cadd	Benign	17
Dann	Benign	0.70
FATHMM_MKL	Benign	0.00098	N
MutationTaster	Benign	1.0	P;P
GERP RS		2.5

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: rs10042074; hg19: chr5-142150942;