5-143207377-A-T

Variant names:

• chr5-143207377-A-T
• rs562055157
• ENST00000274498.9:c.2168A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015071.6(ARHGAP26):​c.2168A>T​(p.His723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H723R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP26 NM_015071.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015071.6. 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>T		intron	N/A	NP_001129080.1	A0A0S2Z536
	ARHGAP26	NM_015071.6		c.2168A>T	p.His723Leu	missense	Exon 21 of 23	NP_055886.1	Q9UNA1-1
	ARHGAP26	NM_001349547.2		c.1881-6620A>T		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>T	p.His723Leu	missense	Exon 21 of 23	ENSP00000274498.4	Q9UNA1-1
	ARHGAP26	ENST00000645722.2	MANE Select	c.2099+69A>T		intron	N/A	ENSP00000495131.1	Q9UNA1-2
	ARHGAP26	ENST00000418236.5	TSL:1	c.702-6620A>T		intron	N/A	ENSP00000416889.1	H0Y835

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.17
Sift	Benign	0.68	T
Sift4G	Benign	0.58	T
Polyphen		0.041	B
Vest4		0.47
MutPred		0.68		Gain of helix (P = 0.0034)
MVP		0.55
MPC		0.84
ClinPred		0.34	T
GERP RS		6.2
PromoterAI		0.024	Neutral
Varity_R		0.16
gMVP		0.47
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs562055157; hg19: chr5-142586942;