17-8312077-C-T

Variant names:

• chr17-8312077-C-T
• rs373751727
• NM_173728.4:c.38C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173728.4(ARHGEF15):​c.38C>T​(p.Thr13Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,418,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. T13P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.31
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12225637).
• BS2: High AC in GnomAdExome4 at 46 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.38C>T	p.Thr13Met	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.38C>T	p.Thr13Met	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.38C>T	p.Thr13Met	missense	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.38C>T	p.Thr13Met	missense	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.38C>T	p.Thr13Met	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.0000277 AC: 4 AN: 144640 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000513

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000214

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000426 AC: 9 AN: 211030 AF XY: 0.0000263

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.0000508

Gnomad NFE exome AF: 0.0000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 46 AN: 1273378 Hom.: 0 Cov.: 35 AF XY: 0.0000395 AC XY: 25 AN XY: 633068

African (AFR) AF: 0.0000382 AC: 1 AN: 26198

American (AMR) AF: 0.00 AC: 0 AN: 32160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17154

East Asian (EAS) AF: 0.000209 AC: 5 AN: 23940

South Asian (SAS) AF: 0.0000390 AC: 3 AN: 76858

European-Finnish (FIN) AF: 0.000120 AC: 5 AN: 41818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4800

European-Non Finnish (NFE) AF: 0.0000269 AC: 27 AN: 1002174

Other (OTH) AF: 0.000104 AC: 5 AN: 48276

GnomAD4 genome AF: 0.0000276 AC: 4 AN: 144762 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 70356

African (AFR) AF: 0.0000512 AC: 2 AN: 39080

American (AMR) AF: 0.00 AC: 0 AN: 14542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.000215 AC: 1 AN: 4656

South Asian (SAS) AF: 0.00 AC: 0 AN: 4350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65974

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.0000912 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

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	0.097
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.050	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		0.96	D
Vest4		0.35
MVP		0.77
MPC		0.21
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.098
gMVP		0.24
Mutation Taster		=97/3	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: rs373751727; hg19: chr17-8215395; COSMIC: COSV62725744; COSMIC: COSV62725744;