NM_173728.4:c.34C>A

Variant names:

• chr17-8312073-C-A
• rs150480540
• NM_173728.4:c.34C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173728.4(ARHGEF15):​c.34C>A​(p.Pro12Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P12A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.34C>A	p.Pro12Thr	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.34C>A	p.Pro12Thr	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.34C>A	p.Pro12Thr	missense	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.34C>A	p.Pro12Thr	missense	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.34C>A	p.Pro12Thr	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000920 AC: 2 AN: 217432 AF XY: 0.0000171

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: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000404 AC: 5 AN: 1237334 Hom.: 0 Cov.: 34 AF XY: 0.00000488 AC XY: 3 AN XY: 614360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25808

American (AMR) AF: 0.00 AC: 0 AN: 33676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16412

East Asian (EAS) AF: 0.00 AC: 0 AN: 21096

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4590

European-Non Finnish (NFE) AF: 0.00000411 AC: 4 AN: 972564

Other (OTH) AF: 0.0000218 AC: 1 AN: 45940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0703568), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.47		Gain of phosphorylation at P12 (P = 0.0106)
MVP		0.88
MPC		0.48
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.34

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: rs150480540; hg19: chr17-8215391; COSMIC: COSV100729975; COSMIC: COSV100729975;