Genetic Variant NM_001135608.3:c.932G>T (chr5-142907803-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001135608.3(ARHGAP26):c.932G>T(p.Gly311Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARHGAP26
NM_001135608.3 missense, splice_region

Scores

Splicing: ADA: 0.01250

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.58

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.120866686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3 link	c.932G>T	p.Gly311Val	missense_variant, splice_region_variant	Exon 9 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.932G>T	p.Gly311Val	missense_variant, splice_region_variant	Exon 9 of 23		NM_001135608.3	ENSP00000495131.1		Q9UNA1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450852

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721922

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

84792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104312

Other (OTH)

AF:

0.00

AC:

AN:

59808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.22

T;.;T;.;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

0.0065

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

.;D;D;D;D;D;D

M_CAP

Benign

0.0060

MetaRNN

Benign

0.12

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.63

N;N;N;.;.;.;.

PhyloP100

2.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

1.4

N;.;N;.;.;N;.

REVEL

Benign

0.063

Sift

Benign

0.53

T;.;T;.;.;T;.

Sift4G

Benign

0.53

T;.;T;.;.;T;.

Polyphen

0.0020

B;B;B;.;.;.;.

Vest4

0.19

MutPred

0.40

Gain of methylation at K310 (P = 0.0375);Gain of methylation at K310 (P = 0.0375);Gain of methylation at K310 (P = 0.0375);.;.;.;.;

MVP

0.24

MPC

1.6

ClinPred

0.83

GERP RS

5.8

PromoterAI

0.0042

Neutral

(source)

Varity_R

0.18

gMVP

0.25

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.020

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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NM_001135608.3:c.932G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over