17-8312078-G-C

Variant names:

• chr17-8312078-G-C
• rs775304849
• NM_173728.4:c.39G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_173728.4(ARHGEF15):​c.39G>C​(p.Thr13Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T13T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• 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 (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-0.018 with no splicing effect.

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.39G>C	p.Thr13Thr	synonymous	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.39G>C	p.Thr13Thr	synonymous	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.39G>C	p.Thr13Thr	synonymous	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.39G>C	p.Thr13Thr	synonymous	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.39G>C	p.Thr13Thr	synonymous	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.000136 AC: 11 AN: 80600 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000276

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 34 AN: 146956 AF XY: 0.000223

Gnomad AFR exome AF: 0.000288

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.000246

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.000347

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000371

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000151 AC: 188 AN: 1242552 Hom.: 0 Cov.: 35 AF XY: 0.000186 AC XY: 113 AN XY: 607130

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

African (AFR) AF: 0.000115 AC: 3 AN: 25980

American (AMR) AF: 0.000606 AC: 14 AN: 23092

Ashkenazi Jewish (ASJ) AF: 0.000218 AC: 4 AN: 18366

East Asian (EAS) AF: 0.000127 AC: 4 AN: 31490

South Asian (SAS) AF: 0.000839 AC: 37 AN: 44108

European-Finnish (FIN) AF: 0.000185 AC: 8 AN: 43216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.000108 AC: 108 AN: 1001440

Other (OTH) AF: 0.000200 AC: 10 AN: 50030

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000136 AC: 11 AN: 80636 Hom.: 0 Cov.: 17 AF XY: 0.0000769 AC XY: 3 AN XY: 39020

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

African (AFR) AF: 0.000103 AC: 2 AN: 19380

American (AMR) AF: 0.000276 AC: 2 AN: 7238

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

East Asian (EAS) AF: 0.000309 AC: 1 AN: 3238

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.000153 AC: 6 AN: 39170

Other (OTH) AF: 0.00 AC: 0 AN: 1046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00225 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.9
DANN	Benign	0.56
PhyloP100		-0.018
Mutation Taster		=100/0	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: rs775304849; hg19: chr17-8215396;