19-1085846-AGGACGG-AGGACGGGGACGG

Variant names:

• chr19-1085846-A-AGGACGG
• rs201348186
• NM_012292.5:c.3263_3268dupGGGACG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4 BS1 BS2

The NM_012292.5(ARHGAP45):​c.3263_3268dupGGGACG​(p.Gly1088_Asp1089dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,611,186 control chromosomes in the GnomAD database, including 49 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0096 (26 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (23 hom.)
• 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: Likely_benign. The variant received -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012292.5.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0096 (1448/150868) while in subpopulation AFR AF = 0.0316 (1274/40276). AF 95% confidence interval is 0.0302. There are 26 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.3263_3268dupGGGACG	p.Gly1088_Asp1089dup	disruptive_inframe_insertion	Exon 23 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.3311_3316dupGGGACG	p.Gly1104_Asp1105dup	disruptive_inframe_insertion	Exon 23 of 23	NP_001245257.1	Q92619-2
	ARHGAP45	NM_001321232.2		c.3275_3280dupGGGACG	p.Gly1092_Asp1093dup	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.3263_3268dupGGGACG	p.Gly1088_Asp1089dup	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000316772.2	Q92619-1
	ARHGAP45	ENST00000586866.5	TSL:1	c.3275_3280dupGGGACG	p.Gly1092_Asp1093dup	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000468615.1	K7ES98
	ARHGAP45	ENST00000885660.1		c.3347_3352dupGGGACG	p.Gly1116_Asp1117dup	disruptive_inframe_insertion	Exon 22 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes AF: 0.00963 AC: 1451 AN: 150748 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00267 AC: 661 AN: 247752 AF XY: 0.00214

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00148

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000350

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00129 AC: 1881 AN: 1460318 Hom.: 23 Cov.: 31 AF XY: 0.00123 AC XY: 894 AN XY: 726508

African (AFR) AF: 0.0329 AC: 1097 AN: 33342

American (AMR) AF: 0.00217 AC: 97 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39606

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86236

European-Finnish (FIN) AF: 0.000267 AC: 14 AN: 52352

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.000317 AC: 353 AN: 1111866

Other (OTH) AF: 0.00254 AC: 153 AN: 60344

GnomAD4 genome AF: 0.00960 AC: 1448 AN: 150868 Hom.: 26 Cov.: 31 AF XY: 0.00927 AC XY: 684 AN XY: 73788

African (AFR) AF: 0.0316 AC: 1274 AN: 40276

American (AMR) AF: 0.00630 AC: 96 AN: 15236

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

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5144

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 67998

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.000479 Hom.: 0

EpiCase AF: 0.000600

EpiControl AF: 0.000415

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;