NM_173728.4:c.266C>A

Variant names:

• chr17-8312305-C-A
• rs375343071
• NM_173728.4:c.266C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173728.4(ARHGEF15):​c.266C>A​(p.Thr89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000692 in 1,560,656 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T89T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000060 (3 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.145
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05725369).
• BS2: High AC in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	NM_173728.4	MANE Select	c.266C>A	p.Thr89Asn	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.266C>A	p.Thr89Asn	missense	Exon 2 of 16	NP_079290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.266C>A	p.Thr89Asn	missense	Exon 2 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.266C>A	p.Thr89Asn	missense	Exon 2 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000579439.5	TSL:5	c.266C>A	p.Thr89Asn	missense	Exon 2 of 3	ENSP00000464540.1

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 23 AN: 149774 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000996

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000796

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000976

GnomAD2 exomes AF: 0.0000424 AC: 9 AN: 212278 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000396

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000197

GnomAD4 exome AF: 0.0000602 AC: 85 AN: 1410882 Hom.: 3 Cov.: 36 AF XY: 0.0000488 AC XY: 34 AN XY: 697116

African (AFR) AF: 0.00 AC: 0 AN: 32276

American (AMR) AF: 0.0000254 AC: 1 AN: 39336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22482

East Asian (EAS) AF: 0.000515 AC: 20 AN: 38814

South Asian (SAS) AF: 0.00 AC: 0 AN: 77760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085414

Other (OTH) AF: 0.00105 AC: 61 AN: 58044

GnomAD4 genome AF: 0.000154 AC: 23 AN: 149774 Hom.: 0 Cov.: 28 AF XY: 0.0000685 AC XY: 5 AN XY: 72990

African (AFR) AF: 0.0000246 AC: 1 AN: 40674

American (AMR) AF: 0.000996 AC: 15 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.000796 AC: 4 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67388

Other (OTH) AF: 0.000976 AC: 2 AN: 2050

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000742 AC: 9

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.14
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.068
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.093	T
Polyphen		0.0	B
Vest4		0.076
MVP		0.68
MPC		0.14
ClinPred		0.31	T
GERP RS		4.0
Varity_R		0.093
gMVP		0.26
Mutation Taster		=96/4	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: rs375343071; hg19: chr17-8215623;