17-38466344-A-G

Position:

• chr17-38466344-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199417.2(ARHGAP23):​c.661A>G​(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGAP23 NM_001199417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.826

Genes affected

ARHGAP23 (HGNC:29293): (Rho GTPase activating protein 23) The RHO (see ARHA; MIM 165390) family of small GTPases are involved in signal transduction through transmembrane receptors, and they are inactive in the GDP-bound form and active in the GTP-bound form. GTPase-activating proteins, such as ARHGAP23, inactivate RHO family proteins by stimulating their hydrolysis of GTP (Katoh and Katoh, 2004 [PubMed 15254754]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08738205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP23	NM_001199417.2	c.661A>G	p.Ser221Gly	missense_variant	7/24	ENST00000622683.5	NP_001186346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP23	ENST00000622683.5	c.661A>G	p.Ser221Gly	missense_variant	7/24	5	NM_001199417.2	ENSP00000481862	P2
ARHGAP23	ENST00000616767.2	c.1003A>G	p.Ser335Gly	missense_variant	7/24	3		ENSP00000516485	A2
ARHGAP23	ENST00000633445.2	c.607A>G	p.Ser203Gly	missense_variant	7/24	3		ENSP00000516484	A2
ARHGAP23	ENST00000620417.4	c.661A>G	p.Ser221Gly	missense_variant	7/25	5		ENSP00000482992	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 33

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

Sep 29, 2023

The c.661A>G (p.S221G) alteration is located in exon 7 (coding exon 7) of the ARHGAP23 gene. This alteration results from a A to G substitution at nucleotide position 661, causing the serine (S) at amino acid position 221 to be replaced by a glycine (G). 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	0.085
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.0071	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.21	T;T
Polyphen		0.14	B;B
Vest4		0.18
MutPred		0.096		Loss of phosphorylation at S221 (P = 0.0047);Loss of phosphorylation at S221 (P = 0.0047);
MVP		0.33
ClinPred		0.13	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-36622585;