5-142932048-C-T

Variant summary

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

The NM_001135608.3(ARHGAP26):​c.1030C>T​(p.Pro344Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARHGAP26
NM_001135608.3 missense, splice_region

Scores

6
13
Splicing: ADA: 0.0001671
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.85

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

Genome browser will be placed here

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=0.21740821).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGAP26NM_001135608.3 linkc.1030C>T p.Pro344Ser missense_variant, splice_region_variant Exon 11 of 23 ENST00000645722.2 NP_001129080.1 Q9UNA1-2A0A0S2Z536

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGAP26ENST00000645722.2 linkc.1030C>T p.Pro344Ser missense_variant, splice_region_variant Exon 11 of 23 NM_001135608.3 ENSP00000495131.1 Q9UNA1-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461702
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727156
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000299
AC:
1
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111862
Other (OTH)
AF:
0.00
AC:
0
AN:
60374
⚠️ 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: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41444
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 05, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1030C>T (p.P344S) alteration is located in exon 11 (coding exon 11) of the ARHGAP26 gene. This alteration results from a C to T substitution at nucleotide position 1030, causing the proline (P) at amino acid position 344 to be replaced by a serine (S). 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
0.11
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.72
D;.;D;.;.;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.86
.;D;T;T;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.22
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L;L;.;.;.
PhyloP100
3.9
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-4.2
D;.;D;.;D;.
REVEL
Benign
0.069
Sift
Benign
0.043
D;.;T;.;D;.
Sift4G
Benign
0.24
T;.;T;.;T;.
Polyphen
0.36
B;B;B;.;.;.
Vest4
0.25
MutPred
0.36
Gain of glycosylation at P344 (P = 0.0492);Gain of glycosylation at P344 (P = 0.0492);Gain of glycosylation at P344 (P = 0.0492);.;.;.;
MVP
0.39
MPC
0.52
ClinPred
0.90
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.51
Mutation Taster
=80/20
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00017
dbscSNV1_RF
Benign
0.054
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

Other links and lift over

dbSNP: rs1028328735; hg19: chr5-142311613; API