Genetic Variant ARHGAP26:p.Ser15Gly (chr5-142770804-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001135608.3(ARHGAP26):c.43A>G(p.Ser15Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ARHGAP26
NM_001135608.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16

Publications

0 publications found

Variant links:

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

ARHGAP26 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3 link	c.43A>G	p.Ser15Gly	missense_variant	Exon 1 of 23	ENST00000645722.2	NP_001129080.1	Q9UNA1-2A0A0S2Z536

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2 link	c.43A>G	p.Ser15Gly	missense_variant	Exon 1 of 23		NM_001135608.3	ENSP00000495131.1		Q9UNA1-2
ARHGAP26	ENST00000274498.9 link	c.43A>G	p.Ser15Gly	missense_variant	Exon 1 of 23	1		ENSP00000274498.4		Q9UNA1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720716

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32184

American (AMR)

AF:

0.00

AC:

AN:

43600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25762

East Asian (EAS)

AF:

0.00

AC:

AN:

37772

South Asian (SAS)

AF:

0.00

AC:

AN:

85172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105376

Other (OTH)

AF:

0.00

AC:

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43A>G (p.S15G) alteration is located in exon 1 (coding exon 1) of the ARHGAP26 gene. This alteration results from a A to G substitution at nucleotide position 43, causing the serine (S) at amino acid position 15 to be replaced by a glycine (G). 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

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

M;M;M

PhyloP100

7.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;D;D

Vest4

0.68

MutPred

0.61

Loss of disorder (P = 0.0637);Loss of disorder (P = 0.0637);Loss of disorder (P = 0.0637);

MVP

0.60

MPC

0.58

ClinPred

0.99

GERP RS

4.4

PromoterAI

-0.067

Neutral

(source)

Varity_R

0.81

gMVP

0.80

Mutation Taster

=61/39

polymorphism

(source)

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

Publications

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5-142770804-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over