10-48446537-T-G

Position:

• chr10-48446537-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021226.4(ARHGAP22):​c.1951A>C​(p.Met651Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M651V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGAP22 NM_021226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

Genes affected

ARHGAP22 (HGNC:30320): (Rho GTPase activating protein 22) This gene encodes a member of the GTPase activating protein family which activates a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues. The result of these interactions is regulation of cell motility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3326025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP22	NM_021226.4	c.1951A>C	p.Met651Leu	missense_variant	10/10	ENST00000249601.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP22	ENST00000249601.9	c.1951A>C	p.Met651Leu	missense_variant	10/10	1	NM_021226.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.1951A>C (p.M651L) alteration is located in exon 10 (coding exon 10) of the ARHGAP22 gene. This alteration results from a A to C substitution at nucleotide position 1951, causing the methionine (M) at amino acid position 651 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.092	T;T;T;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.091	T;T;T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T;T
Polyphen		0.85	P;P;.;.;P;.;P
Vest4		0.45
MutPred		0.38		Loss of helix (P = 3e-04);.;.;.;.;.;.;
MVP		0.49
MPC		0.67
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.23
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs776189077; hg19: chr10-49654580;