5-142907803-G-C

Variant names:

• chr5-142907803-G-C
• rs1598186102
• NM_001135608.3:c.932G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135608.3(ARHGAP26):​c.932G>C​(p.Gly311Ala) variant causes a missense, splice region 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. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G311E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP26 NM_001135608.3 missense, splice_region
• Scores: Splicing: ADA: 0.006252
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14212587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.932G>C	p.Gly311Ala	missense_variant, splice_region_variant	Exon 9 of 23	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.932G>C	p.Gly311Ala	missense_variant, splice_region_variant	Exon 9 of 23		NM_001135608.3	ENSP00000495131.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T;.;T;.;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.0054
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	.;D;T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;.;.;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.61	N;.;N;.;.;N;.
REVEL	Benign	0.063
Sift	Benign	0.51	T;.;T;.;.;T;.
Sift4G	Benign	0.60	T;.;T;.;.;T;.
Polyphen		0.0070	B;B;B;.;.;.;.
Vest4		0.15
MutPred		0.35		Gain of catalytic residue at G311 (P = 0.0407);Gain of catalytic residue at G311 (P = 0.0407);Gain of catalytic residue at G311 (P = 0.0407);.;.;.;.;
MVP		0.55
MPC		1.3
ClinPred		0.63	D
GERP RS		5.8
PromoterAI		0.036	Neutral
Varity_R		0.091
gMVP		0.24
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.096
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: rs1598186102; hg19: chr5-142287368;