17-38462921-A-T

Variant names:

• chr17-38462921-A-T
• rs1262479109
• NM_001199417.2:c.329A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001199417.2(ARHGAP23):​c.329A>T​(p.His110Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H110R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ARHGAP23 NM_001199417.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.57
• Publications: 0 publications found

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]

ENSG00000276170 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199417.2. 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
	ARHGAP23	NM_001199417.2	MANE Select	c.329A>T	p.His110Leu	missense	Exon 4 of 24	NP_001186346.1	Q9P227-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP23	ENST00000622683.5	TSL:5 MANE Select	c.329A>T	p.His110Leu	missense	Exon 4 of 24	ENSP00000481862.1	Q9P227-1
	ARHGAP23	ENST00000616767.2	TSL:3	c.671A>T	p.His224Leu	missense	Exon 4 of 24	ENSP00000516485.1	A0A9L9PXS4
	ARHGAP23	ENST00000633445.2	TSL:3	c.275A>T	p.His92Leu	missense	Exon 4 of 24	ENSP00000516484.1	A0A9L9PXQ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386782 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 684000

African (AFR) AF: 0.00 AC: 0 AN: 30588

American (AMR) AF: 0.00 AC: 0 AN: 30944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24692

East Asian (EAS) AF: 0.00 AC: 0 AN: 35682

South Asian (SAS) AF: 0.00 AC: 0 AN: 76874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075662

Other (OTH) AF: 0.00 AC: 0 AN: 57500

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N
PhyloP100		8.6
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.028	D
Polyphen		0.92	P
Vest4		0.55
MutPred		0.69		Loss of disorder (P = 0.0606)
MVP		0.54
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.74

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: rs1262479109; hg19: chr17-36619162;