5-142901928-A-G

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.598-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,308 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (76 hom.)
• Consequence: ARHGAP26 NM_001135608.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002447
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.628

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=-0.89).
• BP6: Variant 5-142901928-A-G is Benign according to our data. Variant chr5-142901928-A-G is described in ClinVar as [Benign]. Clinvar id is 720303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP26	NM_001135608.3	c.598-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000645722.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.598-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001135608.3	P1
ARHGAP26	ENST00000274498.9	c.598-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
ARHGAP26	ENST00000475287.2	c.370-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
ARHGAP26	ENST00000642734.1	c.490-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2258 AN: 152156 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00390 AC: 980 AN: 250972 Hom.: 27 AF XY: 0.00278 AC XY: 377 AN XY: 135628

Gnomad AFR exome AF: 0.0545

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00156 AC: 2274 AN: 1461034 Hom.: 76 Cov.: 30 AF XY: 0.00137 AC XY: 997 AN XY: 726862

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0149 AC: 2270 AN: 152274 Hom.: 64 Cov.: 32 AF XY: 0.0140 AC XY: 1046 AN XY: 74482

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00756 Hom.: 14

Bravo AF: 0.0166

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.19
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs74628507; hg19: chr5-142281493;