17-8312054-C-T

Variant names:

• chr17-8312054-C-T
• rs1366729811
• NM_173728.4:c.15C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_173728.4(ARHGEF15):​c.15C>T​(p.Ser5Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.208
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-8312054-C-T is Benign according to our data. Variant chr17-8312054-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1645489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.208 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.15C>T	p.Ser5Ser	synonymous	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.15C>T	p.Ser5Ser	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.15C>T	p.Ser5Ser	synonymous	Exon 2 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.15C>T	p.Ser5Ser	synonymous	Exon 2 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.15C>T	p.Ser5Ser	synonymous	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233000 AF XY: 0.00000800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441640 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2 AN XY: 715934

⚠️ 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: 33026

American (AMR) AF: 0.0000701 AC: 3 AN: 42812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24348

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 82890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101676

Other (OTH) AF: 0.00 AC: 0 AN: 59502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.2
DANN	Benign	0.85
PhyloP100		-0.21

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: rs1366729811; hg19: chr17-8215372; COSMIC: COSV62724993; COSMIC: COSV62724993;