NM_173728.4:c.53G>A

Variant names:

• chr17-8312092-G-A
• rs773399469
• NM_173728.4:c.53G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_173728.4(ARHGEF15):​c.53G>A​(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,292,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 16)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• Publications: 0 publications found

Genes affected

ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

ARHGEF15 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000226871 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34616905).
• BS2: High AC in GnomAdExome4 at 23 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173728.4. 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
	ARHGEF15	NM_173728.4	MANE Select	c.53G>A	p.Arg18Gln	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.53G>A	p.Arg18Gln	missense	Exon 2 of 16	NP_079290.1	O94989

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.53G>A	p.Arg18Gln	missense	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.53G>A	p.Arg18Gln	missense	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.53G>A	p.Arg18Gln	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 1 AN: 75704 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000262

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 3 AN: 150940 AF XY: 0.0000363

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000189 AC: 23 AN: 1216988 Hom.: 0 Cov.: 36 AF XY: 0.0000271 AC XY: 16 AN XY: 591254

African (AFR) AF: 0.00 AC: 0 AN: 26082

American (AMR) AF: 0.00 AC: 0 AN: 24360

Ashkenazi Jewish (ASJ) AF: 0.0000547 AC: 1 AN: 18294

East Asian (EAS) AF: 0.00 AC: 0 AN: 31146

South Asian (SAS) AF: 0.0000514 AC: 2 AN: 38914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4790

European-Non Finnish (NFE) AF: 0.0000173 AC: 17 AN: 981970

Other (OTH) AF: 0.0000617 AC: 3 AN: 48610

GnomAD4 genome AF: 0.0000132 AC: 1 AN: 75704 Hom.: 0 Cov.: 16 AF XY: 0.0000277 AC XY: 1 AN XY: 36092

African (AFR) AF: 0.00 AC: 0 AN: 17388

American (AMR) AF: 0.00 AC: 0 AN: 6098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1958

East Asian (EAS) AF: 0.00 AC: 0 AN: 3144

South Asian (SAS) AF: 0.00 AC: 0 AN: 2638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.0000262 AC: 1 AN: 38224

Other (OTH) AF: 0.00 AC: 0 AN: 980

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.60	T
Polyphen		1.0	D
Vest4		0.40
MVP		0.83
MPC		0.45
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.29
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs773399469; hg19: chr17-8215410;