rs1060499743

Variant names:

• chr10-24596030-A-C
• rs1060499743
• NM_020824.4:c.3491T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_020824.4(ARHGAP21):​c.3491T>G​(p.Ile1164Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGAP21 NM_020824.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.23
• Publications: 1 publications found

Genes affected

ARHGAP21 (HGNC:23725): (Rho GTPase activating protein 21) ARHGAP21 functions preferentially as a GTPase-activating protein (GAP) for CDC42 (MIM 116952) and regulates the ARP2/3 complex (MIM 604221) and F-actin dynamics at the Golgi through control of CDC42 activity (Dubois et al., 2005 [PubMed 15793564]).[supplied by OMIM, Mar 2008]

ENSG00000301338 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 10-24596030-A-C is Pathogenic according to our data. Variant chr10-24596030-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402147.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020824.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP21	NM_020824.4	MANE Select	c.3491T>G	p.Ile1164Arg	missense	Exon 18 of 26	NP_065875.3
	ARHGAP21	NM_001367448.1		c.3491T>G	p.Ile1164Arg	missense	Exon 18 of 26	NP_001354377.1
	ARHGAP21	NM_001367454.1		c.3491T>G	p.Ile1164Arg	missense	Exon 18 of 26	NP_001354383.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP21	ENST00000396432.7	TSL:1 MANE Select	c.3491T>G	p.Ile1164Arg	missense	Exon 18 of 26	ENSP00000379709.2
	ARHGAP21	ENST00000680286.1		c.3512T>G	p.Ile1171Arg	missense	Exon 17 of 25	ENSP00000506388.1
	ARHGAP21	ENST00000376410.7	TSL:5	c.3461T>G	p.Ile1154Arg	missense	Exon 17 of 25	ENSP00000365592.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.25	T
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.90
MVP		0.67
MPC		3.5
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.011	Neutral
gMVP		0.98
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs1060499743; hg19: chr10-24884959;