ENST00000274498.9:c.2168A>G

Variant names:

• chr5-143207377-A-G
• rs562055157
• ENST00000274498.9:c.2168A>G
• ARHGAP26 p.His723Arg

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000274498.9(ARHGAP26):​c.2168A>G​(p.His723Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,613,960 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (7 hom.)
• Consequence: ARHGAP26 ENST00000274498.9 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.42
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008408189).
• BS2: High Homozygotes in GnomAdExome4 at 7 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000274498.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP26	NM_001135608.3	MANE Select	c.2099+69A>G		intron	N/A	NP_001129080.1	A0A0S2Z536
	ARHGAP26	NM_015071.6		c.2168A>G	p.His723Arg	missense	Exon 21 of 23	NP_055886.1	Q9UNA1-1
	ARHGAP26	NM_001349547.2		c.1881-6620A>G		intron	N/A	NP_001336476.1	A0A2R8YGB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP26	ENST00000274498.9	TSL:1	c.2168A>G	p.His723Arg	missense	Exon 21 of 23	ENSP00000274498.4	Q9UNA1-1
	ARHGAP26	ENST00000645722.2	MANE Select	c.2099+69A>G		intron	N/A	ENSP00000495131.1	Q9UNA1-2
	ARHGAP26	ENST00000418236.5	TSL:1	c.702-6620A>G		intron	N/A	ENSP00000416889.1	H0Y835

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00666

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000688 AC: 173 AN: 251386 AF XY: 0.000942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000383 AC: 560 AN: 1461890 Hom.: 7 Cov.: 32 AF XY: 0.000545 AC XY: 396 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00621 AC: 536 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00667 AC: 32 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.14
Sift	Benign	0.53	T
Sift4G	Benign	0.47	T
PromoterAI		0.046	Neutral
Varity_R		0.18
gMVP		0.40
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs562055157;

hg19: chr5-142586942;