rs1060503817

Variant names:

• chr17-8313079-T-C
• rs1060503817
• NM_173728.4:c.759T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-8313079-T-C
• chr17-8313079-T-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_173728.4(ARHGEF15):​c.759T>C​(p.Pro253Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00900
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-8313079-T-C is Benign according to our data. Variant chr17-8313079-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 412669.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.009 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.759T>C	p.Pro253Pro	synonymous	Exon 3 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.759T>C	p.Pro253Pro	synonymous	Exon 3 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.759T>C	p.Pro253Pro	synonymous	Exon 3 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.759T>C	p.Pro253Pro	synonymous	Exon 3 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.759T>C	p.Pro253Pro	synonymous	Exon 3 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 108 AN: 82946 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00207

Gnomad AMR AF: 0.00117

Gnomad ASJ AF: 0.000919

Gnomad EAS AF: 0.000335

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.00174

GnomAD2 exomes AF: 0.0118 AC: 2590 AN: 219840 AF XY: 0.0108

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.00460

Gnomad FIN exome AF: 0.00850

Gnomad NFE exome AF: 0.00631

Gnomad OTH exome AF: 0.0167

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00517 AC: 4307 AN: 833250 Hom.: 0 Cov.: 34 AF XY: 0.00490 AC XY: 2070 AN XY: 422716

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

African (AFR) AF: 0.00993 AC: 212 AN: 21344

American (AMR) AF: 0.0510 AC: 1682 AN: 32988

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 501 AN: 16438

East Asian (EAS) AF: 0.000384 AC: 10 AN: 26044

South Asian (SAS) AF: 0.00616 AC: 374 AN: 60704

European-Finnish (FIN) AF: 0.00702 AC: 255 AN: 36320

Middle Eastern (MID) AF: 0.00407 AC: 16 AN: 3930

European-Non Finnish (NFE) AF: 0.00174 AC: 1046 AN: 601374

Other (OTH) AF: 0.00619 AC: 211 AN: 34108

⚠️ 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: 0.00130 AC: 108 AN: 82980 Hom.: 0 Cov.: 26 AF XY: 0.00133 AC XY: 53 AN XY: 39732

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

African (AFR) AF: 0.00123 AC: 27 AN: 21984

American (AMR) AF: 0.00117 AC: 9 AN: 7696

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 2 AN: 2176

East Asian (EAS) AF: 0.000336 AC: 1 AN: 2976

South Asian (SAS) AF: 0.000425 AC: 1 AN: 2354

European-Finnish (FIN) AF: 0.00110 AC: 5 AN: 4528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 148

European-Non Finnish (NFE) AF: 0.00152 AC: 60 AN: 39468

Other (OTH) AF: 0.00172 AC: 2 AN: 1166

⚠️ 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: 0.0237 Hom.: 0

ClinVar

ClinVar submissions

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	-0.77
CADD	Benign	7.7
DANN	Benign	0.45
PhyloP100		-0.0090
PromoterAI		-0.014	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060503817; hg19: chr17-8216397;