17-8312076-A-G

Variant names:

• chr17-8312076-A-G
• rs1366405067
• NM_173728.4:c.37A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173728.4(ARHGEF15):​c.37A>G​(p.Thr13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000992 in 1,008,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T13M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13487259).

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.37A>G	p.Thr13Ala	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.37A>G	p.Thr13Ala	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.37A>G	p.Thr13Ala	missense	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.37A>G	p.Thr13Ala	missense	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.37A>G	p.Thr13Ala	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 9.92e-7 AC: 1 AN: 1008482 Hom.: 0 Cov.: 33 AF XY: 0.00000201 AC XY: 1 AN XY: 496418

⚠️ 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: 19802

American (AMR) AF: 0.00 AC: 0 AN: 21934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11660

East Asian (EAS) AF: 0.00 AC: 0 AN: 14898

South Asian (SAS) AF: 0.00 AC: 0 AN: 51802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3764

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818748

Other (OTH) AF: 0.00 AC: 0 AN: 36286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.27
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.032
Sift	Benign	0.069	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.30		Loss of phosphorylation at T13 (P = 0.0024)
MVP		0.70
MPC		0.082
ClinPred		0.26	T
GERP RS		2.4
Varity_R		0.040
gMVP		0.23

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: rs1366405067; hg19: chr17-8215394;