chr5-142771377-T-C

Variant names:

• chr5-142771377-T-C
• rs10042074
• NM_001135608.3:c.154+462T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (13941 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14924 hom.)
• Consequence: ARHGAP26 NM_001135608.3 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00700
• Publications: 7 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 -13 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.154+462T>C		intron_variant	Intron 1 of 22	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.154+462T>C		intron_variant	Intron 1 of 22		NM_001135608.3	ENSP00000495131.1
ARHGAP26	ENST00000274498.9	c.154+462T>C		intron_variant	Intron 1 of 22	1		ENSP00000274498.4
ARHGAP26	ENST00000642734.1	c.46+2T>C		splice_donor_variant, intron_variant	Intron 1 of 21			ENSP00000495827.1

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

African (AFR) AF: 0.804 AC: 18468 AN: 22964

American (AMR) AF: 0.267 AC: 2250 AN: 8422

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 2147 AN: 14392

East Asian (EAS) AF: 0.351 AC: 9320 AN: 26524

South Asian (SAS) AF: 0.210 AC: 4112 AN: 19618

European-Finnish (FIN) AF: 0.131 AC: 2757 AN: 21106

Middle Eastern (MID) AF: 0.244 AC: 711 AN: 2916

European-Non Finnish (NFE) AF: 0.0871 AC: 80164 AN: 920192

Other (OTH) AF: 0.179 AC: 7839 AN: 43686

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

African (AFR) AF: 0.770 AC: 31947 AN: 41494

American (AMR) AF: 0.268 AC: 4089 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3470

East Asian (EAS) AF: 0.366 AC: 1885 AN: 5150

South Asian (SAS) AF: 0.222 AC: 1073 AN: 4826

European-Finnish (FIN) AF: 0.134 AC: 1413 AN: 10576

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.0912 AC: 6198 AN: 67932

Other (OTH) AF: 0.284 AC: 596 AN: 2102

Alfa AF: 0.231 Hom.: 1245

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: no assertion criteria provided

Submissions by phenotype

ARHGAP26-related disorder Benign:1

May 10, 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	-0.87
CADD	Benign	17
DANN	Benign	0.70
FATHMM_MKL	Benign	0.00098	N
PhyloP100		-0.0070
GERP RS		2.5
PromoterAI		0.13	Neutral
Mutation Taster		=100/0	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: rs10042074; hg19: chr5-142150942;