NM_181335.3:c.878-2100A>G

Variant names:

• chr22-44857631-A-G
• rs6007334
• NM_181335.3:c.878-2100A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181335.3(ARHGAP8):​c.878-2100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,000 control chromosomes in the GnomAD database, including 2,165 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2165 hom., cov: 32)
• Consequence: ARHGAP8 NM_181335.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 1 publications found

Genes affected

ARHGAP8 (HGNC:677): (Rho GTPase activating protein 8) This gene encodes a member of the RHOGAP family. GAP (GTPase-activating) family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. GAP proteins alternate between an active (GTP-bound) and inactive (GDP-bound) state based on the GTP:GDP ratio in the cell. This family member is a multidomain protein that functions to promote Erk activation and cell motility. Alternative splicing results in multiple transcript variants. Read-through transcripts from the upstream proline rich 5, renal (PRR5) gene into this gene also exist, which led to the original description of PRR5 and ARHGAP8 being a single gene. [provided by RefSeq, Nov 2010]

PRR5-ARHGAP8 (HGNC:34512): (PRR5-ARHGAP8 readthrough) The PRR5-ARHGAP8 mRNA is an infrequent but naturally occurring read-through transcript of the neighboring proline rich 5, renal (PRR5) and Rho GTPase activating protein 8 (ARHGAP8) genes. The resulting fusion protein contains sequence identity with each individual gene product, and it includes domains characteristic of a RhoGAP protein. The significance of this read-through transcript and the function of its protein product have not yet been determined. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP8	NM_181335.3	MANE Select	c.878-2100A>G		intron	N/A	NP_851852.2
	PRR5-ARHGAP8	NM_181334.6		c.1271-2100A>G		intron	N/A	NP_851851.3
	ARHGAP8	NM_001017526.2		c.971-2100A>G		intron	N/A	NP_001017526.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP8	ENST00000356099.11	TSL:1 MANE Select	c.878-2100A>G		intron	N/A	ENSP00000348407.6
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.1508-2100A>G		intron	N/A	ENSP00000262731.11
	ARHGAP8	ENST00000336963.8	TSL:1	c.878-4644A>G		intron	N/A	ENSP00000337287.4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22530 AN: 151882 Hom.: 2158 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.115

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22577 AN: 152000 Hom.: 2165 Cov.: 32 AF XY: 0.145 AC XY: 10761 AN XY: 74324

African (AFR) AF: 0.276 AC: 11434 AN: 41404

American (AMR) AF: 0.0816 AC: 1246 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 362 AN: 3470

East Asian (EAS) AF: 0.0122 AC: 63 AN: 5168

South Asian (SAS) AF: 0.0715 AC: 344 AN: 4810

European-Finnish (FIN) AF: 0.113 AC: 1199 AN: 10594

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7554 AN: 67972

Other (OTH) AF: 0.116 AC: 245 AN: 2112

Alfa AF: 0.136 Hom.: 229

Bravo AF: 0.152

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.81
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs6007334; hg19: chr22-45253511;