5-142901928-A-G

Variant names:

• chr5-142901928-A-G
• rs74628507
• NM_001135608.3:c.598-7A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00002447
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.628
• Publications: 1 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=-0.89).
• 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 rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.598-7A>G		splice_region_variant, intron_variant	Intron 6 of 22	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.598-7A>G		splice_region_variant, intron_variant	Intron 6 of 22		NM_001135608.3	ENSP00000495131.1
ARHGAP26	ENST00000274498.9	c.598-7A>G		splice_region_variant, intron_variant	Intron 6 of 22	1		ENSP00000274498.4
ARHGAP26	ENST00000642734.1	c.490-7A>G		splice_region_variant, intron_variant	Intron 6 of 21			ENSP00000495827.1
ARHGAP26	ENST00000475287.2	c.370-7A>G		splice_region_variant, intron_variant	Intron 4 of 8	5		ENSP00000494415.1

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

GnomAD2 exomes AF: 0.00390 AC: 980 AN: 250972 AF XY: 0.00278

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 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

African (AFR) AF: 0.0552 AC: 1847 AN: 33446

American (AMR) AF: 0.00251 AC: 112 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111398

Other (OTH) AF: 0.00373 AC: 225 AN: 60356

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

African (AFR) AF: 0.0522 AC: 2167 AN: 41530

American (AMR) AF: 0.00484 AC: 74 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00795 Hom.: 15

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

Jan 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.61
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74628507; hg19: chr5-142281493;