19-1085846-AGGACGG-AGGACGGGGACGGGGACGGGGACGG

Variant names:

• chr19-1085846-A-AGGACGGGGACGGGGACGG
• rs201348186
• NM_012292.5:c.3268_3269insGGGACGGGGACGGGGACG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_012292.5(ARHGAP45):​c.3268_3269insGGGACGGGGACGGGGACG​(p.Asp1089_Glu1090insGlyAspGlyAspGlyAsp) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000531 in 150,756 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000053 (0 hom., cov: 31)
• Consequence: ARHGAP45 NM_012292.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 0 publications found

Genes affected

ARHGAP45 (HGNC:17102): (Rho GTPase activating protein 45) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

POLR2E (HGNC:9192): (RNA polymerase II, I and III subunit E) This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012292.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012292.5. 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
	ARHGAP45	NM_012292.5	MANE Select	c.3268_3269insGGGACGGGGACGGGGACG	p.Asp1089_Glu1090insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 23 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.3316_3317insGGGACGGGGACGGGGACG	p.Asp1105_Glu1106insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 23 of 23	NP_001245257.1	Q92619-2
	ARHGAP45	NM_001321232.2		c.3280_3281insGGGACGGGGACGGGGACG	p.Asp1093_Glu1094insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 23 of 23	NP_001308161.1	K7ES98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.3268_3269insGGGACGGGGACGGGGACG	p.Asp1089_Glu1090insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000316772.2	Q92619-1
	ARHGAP45	ENST00000586866.5	TSL:1	c.3280_3281insGGGACGGGGACGGGGACG	p.Asp1093_Glu1094insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000468615.1	K7ES98
	ARHGAP45	ENST00000885660.1		c.3352_3353insGGGACGGGGACGGGGACG	p.Asp1117_Glu1118insGlyAspGlyAspGlyAsp	disruptive_inframe_insertion	Exon 22 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150756 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247752 AF XY: 0.00

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.00

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 Cov.: 31

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150756 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73660

African (AFR) AF: 0.000199 AC: 8 AN: 40160

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201348186; hg19: chr19-1085845;