5-143214082-G-T

Variant names:

• chr5-143214082-G-T
• rs587778049
• NM_001135608.3:c.2185G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001135608.3(ARHGAP26):​c.2185G>T​(p.Asp729Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,210,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. D729N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: ARHGAP26 NM_001135608.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26957464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP26	NM_001135608.3	c.2185G>T	p.Asp729Tyr	missense_variant	Exon 22 of 23	ENST00000645722.2	NP_001129080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP26	ENST00000645722.2	c.2185G>T	p.Asp729Tyr	missense_variant	Exon 22 of 23		NM_001135608.3	ENSP00000495131.1
ARHGAP26	ENST00000425417.2	c.193G>T	p.Asp65Tyr	missense_variant	Exon 2 of 3	5		ENSP00000403388.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1210714 Hom.: 0 Cov.: 26 AF XY: 0.00000334 AC XY: 2 AN XY: 598024

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

African (AFR) AF: 0.00 AC: 0 AN: 27678

American (AMR) AF: 0.00 AC: 0 AN: 36990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18806

East Asian (EAS) AF: 0.00 AC: 0 AN: 23806

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4718

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 938042

Other (OTH) AF: 0.00 AC: 0 AN: 46040

⚠️ 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.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.11	N;.;N;.
PhyloP100		5.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.013	D;.;.;.
Sift4G	Benign	0.45	T;.;.;.
Polyphen		0.91	P;P;P;.
Vest4		0.44
MutPred		0.42		Loss of disorder (P = 0.0727);.;Loss of disorder (P = 0.0727);.;
MVP		0.42
MPC		1.3
ClinPred		0.80	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.82
Mutation Taster		=43/57	disease causing

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

dbSNP: rs587778049; hg19: chr5-142593647;