22-44809096-C-T

Variant names:

• chr22-44809096-C-T
• rs559051849
• NM_181335.3:c.299+658C>T

Variant summary

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

The NM_001017526.2(ARHGAP8):​c.390C>T​(p.Tyr130Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 470,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: ARHGAP8 NM_001017526.2 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.379
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-44809096-C-T is Benign according to our data. Variant chr22-44809096-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2653278.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017526.2. 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
	ARHGAP8	NM_181335.3	MANE Select	c.299+658C>T		intron	N/A	NP_851852.2	P85298-4
	ARHGAP8	NM_001017526.2		c.390C>T	p.Tyr130Tyr	splice_region synonymous	Exon 5 of 13	NP_001017526.1	P85298-1
	PRR5-ARHGAP8	NM_181334.6		c.692+658C>T		intron	N/A	NP_851851.3	B1AHC3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP8	ENST00000356099.11	TSL:1 MANE Select	c.299+658C>T		intron	N/A	ENSP00000348407.6	P85298-4
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.930-5576C>T		intron	N/A	ENSP00000262731.11	B1AHC4
	ARHGAP8	ENST00000336963.8	TSL:1	c.299+658C>T		intron	N/A	ENSP00000337287.4	P85298-5

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000743 AC: 110 AN: 148080 AF XY: 0.000676

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000651

Gnomad ASJ exome AF: 0.000359

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000618

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.000814 AC: 259 AN: 318144 Hom.: 1 Cov.: 0 AF XY: 0.000851 AC XY: 153 AN XY: 179820

African (AFR) AF: 0.000116 AC: 1 AN: 8620

American (AMR) AF: 0.000623 AC: 17 AN: 27282

Ashkenazi Jewish (ASJ) AF: 0.000185 AC: 2 AN: 10788

East Asian (EAS) AF: 0.00 AC: 0 AN: 9214

South Asian (SAS) AF: 0.000486 AC: 29 AN: 59726

European-Finnish (FIN) AF: 0.000150 AC: 4 AN: 26724

Middle Eastern (MID) AF: 0.00119 AC: 3 AN: 2518

European-Non Finnish (NFE) AF: 0.00118 AC: 188 AN: 158984

Other (OTH) AF: 0.00105 AC: 15 AN: 14288

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74412

African (AFR) AF: 0.000217 AC: 9 AN: 41532

American (AMR) AF: 0.00177 AC: 27 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000805

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.9
DANN	Benign	0.58
PhyloP100		0.38
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: rs559051849; hg19: chr22-45204976;