5-142902018-G-C

Variant names:

• chr5-142902018-G-C
• NM_001135608.3:c.681G>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.681G>C​(p.Gln227His) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP26 NM_001135608.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• 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=0.15617427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.681G>C	p.Gln227His	missense_variant	Exon 7 of 23	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.681G>C	p.Gln227His	missense_variant	Exon 7 of 23		NM_001135608.3	ENSP00000495131.1
ARHGAP26	ENST00000274498.9	c.681G>C	p.Gln227His	missense_variant	Exon 7 of 23	1		ENSP00000274498.4
ARHGAP26	ENST00000642734.1	c.573G>C	p.Gln191His	missense_variant	Exon 7 of 22			ENSP00000495827.1
ARHGAP26	ENST00000475287.2	c.453G>C	p.Gln151His	missense_variant	Exon 5 of 9	5		ENSP00000494415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.681G>C (p.Q227H) alteration is located in exon 7 (coding exon 7) of the ARHGAP26 gene. This alteration results from a G to C substitution at nucleotide position 681, causing the glutamine (Q) at amino acid position 227 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;.;.
PhyloP100		1.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;.;D;.;.
REVEL	Benign	0.038
Sift	Uncertain	0.0020	D;.;D;.;.
Sift4G	Uncertain	0.0050	D;.;T;.;.
Polyphen		0.92	P;B;P;.;.
Vest4		0.27
MutPred		0.29		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;.;
MVP		0.42
MPC		0.92
ClinPred		0.92	D
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.44
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

Other links and lift over

hg19: chr5-142281583;