chr10-48450493-C-A

Variant names:

• chr10-48450493-C-A
• rs756521559
• NM_021226.4:c.1636G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021226.4(ARHGAP22):​c.1636G>T​(p.Asp546Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,380,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. D546H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ARHGAP22 NM_021226.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44
• Publications: 0 publications found

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

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=0.22877693).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021226.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP22	NM_021226.4	MANE Select	c.1636G>T	p.Asp546Tyr	missense	Exon 9 of 10	NP_067049.2
	ARHGAP22	NM_001256024.2		c.1684G>T	p.Asp562Tyr	missense	Exon 9 of 10	NP_001242953.1	Q7Z5H3-2
	ARHGAP22	NM_001256025.3		c.1654G>T	p.Asp552Tyr	missense	Exon 9 of 10	NP_001242954.1	Q7Z5H3-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP22	ENST00000249601.9	TSL:1 MANE Select	c.1636G>T	p.Asp546Tyr	missense	Exon 9 of 10	ENSP00000249601.4	Q7Z5H3-1
	ARHGAP22	ENST00000417912.6	TSL:1	c.1684G>T	p.Asp562Tyr	missense	Exon 9 of 10	ENSP00000412461.2	Q7Z5H3-2
	ARHGAP22	ENST00000477708.6	TSL:1	c.1135G>T	p.Asp379Tyr	missense	Exon 1 of 2	ENSP00000422868.1	D6R9V6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380128 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 677944

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 35338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23638

East Asian (EAS) AF: 0.00 AC: 0 AN: 36118

South Asian (SAS) AF: 0.00 AC: 0 AN: 75512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1070632

Other (OTH) AF: 0.0000175 AC: 1 AN: 57148

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.029	D
Polyphen		0.60	P
Vest4		0.27
MutPred		0.25		Gain of helix (P = 0.0117)
MVP		0.57
MPC		0.63
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.43
gMVP		0.30
Mutation Taster		=93/7	polymorphism

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: rs756521559; hg19: chr10-49658536;