NM_001366178.1:c.724T>C

Variant names:

• chr19-35780603-T-C
• rs1324847898
• NM_001366178.1:c.724T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001366178.1(ARHGAP33):​c.724T>C​(p.Cys242Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000809 in 1,607,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARHGAP33 NM_001366178.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• Publications: 0 publications found

Genes affected

ARHGAP33 (HGNC:23085): (Rho GTPase activating protein 33) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. Alternative splice variants encoding different isoforms have been identified in this gene. [provided by RefSeq, Feb 2010]

ARHGAP33 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366178.1. 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
	ARHGAP33	NM_001366178.1	MANE Select	c.724T>C	p.Cys242Arg	missense	Exon 9 of 21	NP_001353107.1	O14559-1
	ARHGAP33	NM_052948.4		c.724T>C	p.Cys242Arg	missense	Exon 9 of 21	NP_443180.2
	ARHGAP33	NM_001172630.2		c.316T>C	p.Cys106Arg	missense	Exon 8 of 21	NP_001166101.1	O14559-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP33	ENST00000007510.9	TSL:5 MANE Select	c.724T>C	p.Cys242Arg	missense	Exon 9 of 21	ENSP00000007510.6	O14559-1
	ARHGAP33	ENST00000314737.9	TSL:2	c.724T>C	p.Cys242Arg	missense	Exon 9 of 21	ENSP00000320038.4	O14559-11
	ARHGAP33	ENST00000378944.9	TSL:2	c.316T>C	p.Cys106Arg	missense	Exon 8 of 21	ENSP00000368227.5	O14559-10

Frequencies

GnomAD3 genomes AF: 0.0000611 AC: 9 AN: 147398 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000541

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460316 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 726458

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000672 AC: 3 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111182

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome AF: 0.0000611 AC: 9 AN: 147398 Hom.: 0 Cov.: 31 AF XY: 0.0000699 AC XY: 5 AN XY: 71582

African (AFR) AF: 0.00 AC: 0 AN: 39728

American (AMR) AF: 0.000541 AC: 8 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67062

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.87		Gain of disorder (P = 0.0124)
MVP		0.59
MPC		1.6
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.98
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1324847898; hg19: chr19-36271505;