Genetic Variant NM_012292.5:c.3096G>A (chr19-1085691-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012292.5(ARHGAP45):c.3096G>A(p.Ser1032Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,590,752 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 7 hom., cov: 31)

Exomes 𝑓: 0.00078 ( 12 hom. )

Consequence

ARHGAP45
NM_012292.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.77

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-1085691-G-A is Benign according to our data. Variant chr19-1085691-G-A is described in ClinVar as Benign. ClinVar VariationId is 717572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00722 (1086/150314) while in subpopulation AFR AF = 0.0251 (1029/41002). AF 95% confidence interval is 0.0238. There are 7 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.3096G>A	p.Ser1032Ser	synonymous	Exon 23 of 23	NP_036424.2
ARHGAP45	NM_001258328.4		c.3144G>A	p.Ser1048Ser	synonymous	Exon 23 of 23	NP_001245257.1	Q92619-2
ARHGAP45	NM_001321232.2		c.3108G>A	p.Ser1036Ser	synonymous	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.3096G>A	p.Ser1032Ser	synonymous	Exon 23 of 23	ENSP00000316772.2	Q92619-1
ARHGAP45	ENST00000586866.5	TSL:1	c.3108G>A	p.Ser1036Ser	synonymous	Exon 23 of 23	ENSP00000468615.1	K7ES98
ARHGAP45	ENST00000885660.1		c.3180G>A	p.Ser1060Ser	synonymous	Exon 22 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes

AF:

0.00722

AC:

1085

AN:

150190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00194

Gnomad ASJ

AF:

0.00174

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00532

GnomAD2 exomes

AF:

0.00182

AC:

425

AN:

234088

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000352

GnomAD4 exome

AF:

0.000781

AC:

1125

AN:

1440438

Hom.:

Cov.:

AF XY:

0.000680

AC XY:

485

AN XY:

713516

show subpopulations

African (AFR)

AF:

0.0254

AC:

837

AN:

32934

American (AMR)

AF:

0.00122

AC:

AN:

42784

Ashkenazi Jewish (ASJ)

AF:

0.00106

AC:

AN:

25466

East Asian (EAS)

AF:

0.00

AC:

AN:

39180

South Asian (SAS)

AF:

0.000129

AC:

AN:

84958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51884

Middle Eastern (MID)

AF:

0.00281

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000692

AC:

AN:

1098214

Other (OTH)

AF:

0.00179

AC:

106

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00722

AC:

1086

AN:

150314

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

498

AN XY:

73356

show subpopulations

African (AFR)

AF:

0.0251

AC:

1029

AN:

41002

American (AMR)

AF:

0.00193

AC:

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.000213

AC:

AN:

4696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67376

Other (OTH)

AF:

0.00526

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.00837

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0060

(source)

DANN

Benign

0.89

PhyloP100

-3.8

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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