rs1060503817

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-8313079-T-A
• chr17-8313079-T-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.759T>A​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P253P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• 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=-0.73).
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.759T>A	p.Pro253Pro	synonymous_variant	Exon 3 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.759T>A	p.Pro253Pro	synonymous_variant	Exon 3 of 16	1	NM_173728.4	ENSP00000355026.3

Frequencies

GnomAD3 genomes AF: 0.0000599 AC: 5 AN: 83440 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.000220

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000503

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00156 AC: 1304 AN: 834222 Hom.: 0 Cov.: 34 AF XY: 0.00149 AC XY: 633 AN XY: 423668

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

African (AFR) AF: 0.00111 AC: 24 AN: 21572

American (AMR) AF: 0.0000868 AC: 3 AN: 34566

Ashkenazi Jewish (ASJ) AF: 0.000658 AC: 11 AN: 16708

East Asian (EAS) AF: 0.0000767 AC: 2 AN: 26070

South Asian (SAS) AF: 0.000418 AC: 26 AN: 62162

European-Finnish (FIN) AF: 0.000272 AC: 10 AN: 36798

Middle Eastern (MID) AF: 0.000253 AC: 1 AN: 3956

European-Non Finnish (NFE) AF: 0.00197 AC: 1181 AN: 598074

Other (OTH) AF: 0.00134 AC: 46 AN: 34316

⚠️ 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: 0.0000599 AC: 5 AN: 83474 Hom.: 0 Cov.: 26 AF XY: 0.000100 AC XY: 4 AN XY: 39952

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

African (AFR) AF: 0.0000453 AC: 1 AN: 22086

American (AMR) AF: 0.00 AC: 0 AN: 7748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2180

East Asian (EAS) AF: 0.00 AC: 0 AN: 2978

South Asian (SAS) AF: 0.000424 AC: 1 AN: 2360

European-Finnish (FIN) AF: 0.000220 AC: 1 AN: 4550

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

European-Non Finnish (NFE) AF: 0.0000503 AC: 2 AN: 39766

Other (OTH) AF: 0.00 AC: 0 AN: 1170

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000108802), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.5
DANN	Benign	0.60
PhyloP100		-0.0090
PromoterAI		0.0048	Neutral

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: rs1060503817; hg19: chr17-8216397;