Genetic Variant ARHGAP45:p.Gly1086_Asp1089dup (chr19-1085846-A-AGGACGGGGACGG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM4BP6_ModerateBS1BS2

The NM_012292.5(ARHGAP45):c.3257_3268dupGGGACGGGGACG(p.Gly1086_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 0.000827 in 1,611,188 control chromosomes in the GnomAD database, including 11 homozygotes. 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. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00050 ( 6 hom. )

Consequence

ARHGAP45
NM_012292.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.35

Publications

0 publications found

Variant links:

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]

ARHGAP45 links:

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]

POLR2E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_012292.5.

BP6

Variant 19-1085846-A-AGGACGGGGACGG is Benign according to our data. Variant chr19-1085846-A-AGGACGGGGACGG is described in ClinVar as Benign. ClinVar VariationId is 710671.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000497 (726/1460318) while in subpopulation AFR AF = 0.0183 (611/33342). AF 95% confidence interval is 0.0171. There are 6 homozygotes in GnomAdExome4. There are 283 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP45	NM_012292.5	MANE Select	c.3257_3268dupGGGACGGGGACG	p.Gly1086_Asp1089dup	disruptive_inframe_insertion	Exon 23 of 23	NP_036424.2
ARHGAP45	NM_001258328.4		c.3305_3316dupGGGACGGGGACG	p.Gly1102_Asp1105dup	disruptive_inframe_insertion	Exon 23 of 23	NP_001245257.1	Q92619-2
ARHGAP45	NM_001321232.2		c.3269_3280dupGGGACGGGGACG	p.Gly1090_Asp1093dup	disruptive_inframe_insertion	Exon 23 of 23	NP_001308161.1	K7ES98

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.3257_3268dupGGGACGGGGACG	p.Gly1086_Asp1089dup	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000316772.2	Q92619-1
ARHGAP45	ENST00000586866.5	TSL:1	c.3269_3280dupGGGACGGGGACG	p.Gly1090_Asp1093dup	disruptive_inframe_insertion	Exon 23 of 23	ENSP00000468615.1	K7ES98
ARHGAP45	ENST00000885660.1		c.3341_3352dupGGGACGGGGACG	p.Gly1114_Asp1117dup	disruptive_inframe_insertion	Exon 22 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

604

AN:

150750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000986

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00102

AC:

253

AN:

247752

AF XY:

0.000763

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.000497

AC:

726

AN:

1460318

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

283

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.0183

AC:

611

AN:

33342

American (AMR)

AF:

0.000559

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52352

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111866

Other (OTH)

AF:

0.000878

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00402

AC:

607

AN:

150870

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

313

AN XY:

73788

show subpopulations

African (AFR)

AF:

0.0145

AC:

585

AN:

40274

American (AMR)

AF:

0.000984

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000736

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over