rs3749130

Variant names:

• chr2-68807383-C-T
• rs3749130
• NM_001007231.3:c.577C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001007231.3(ARHGAP25):​c.577C>T​(p.Arg193Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,614,208 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. R193Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (19 hom.)
• Consequence: ARHGAP25 NM_001007231.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 6 publications found

Genes affected

ARHGAP25 (HGNC:28951): (Rho GTPase activating protein 25) ARHGAPs, such as ARHGAP25, encode negative regulators of Rho GTPases (see ARHA; MIM 165390), which are implicated in actin remodeling, cell polarity, and cell migration (Katoh and Katoh, 2004 [PubMed 15254788]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004926592).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000746 (1091/1461882) while in subpopulation EAS AF = 0.0271 (1077/39700). AF 95% confidence interval is 0.0258. There are 19 homozygotes in GnomAdExome4. There are 533 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007231.3. 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
	ARHGAP25	NM_001007231.3	MANE Select	c.577C>T	p.Arg193Trp	missense	Exon 5 of 11	NP_001007232.2	P42331-4
	ARHGAP25	NM_001364819.1		c.574C>T	p.Arg192Trp	missense	Exon 5 of 11	NP_001351748.1	P42331-1
	ARHGAP25	NM_001166276.2		c.556C>T	p.Arg186Trp	missense	Exon 4 of 10	NP_001159748.1	P42331-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP25	ENST00000409202.8	TSL:2 MANE Select	c.577C>T	p.Arg193Trp	missense	Exon 5 of 11	ENSP00000386911.3	P42331-4
	ARHGAP25	ENST00000409220.5	TSL:1	c.556C>T	p.Arg186Trp	missense	Exon 4 of 10	ENSP00000386241.1	P42331-6
	ARHGAP25	ENST00000409030.7	TSL:1	c.553C>T	p.Arg185Trp	missense	Exon 4 of 10	ENSP00000386863.3	P42331-3

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152208 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000430 AC: 108 AN: 251388 AF XY: 0.000478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000746 AC: 1091 AN: 1461882 Hom.: 19 Cov.: 31 AF XY: 0.000733 AC XY: 533 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0271 AC: 1077 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152326 Hom.: 3 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000244 Hom.: 4

Bravo AF: 0.000147

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.093
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.85	P
Vest4		0.23
MVP		0.33
MPC		0.52
ClinPred		0.13	T
GERP RS		2.1
PromoterAI		-0.019	Neutral
gMVP		0.67
Mutation Taster		=98/2	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: rs3749130; hg19: chr2-69034515; COSMIC: COSV99772281;