Genetic Variant ARHGAP45:c.-80C>T (chr19-1065946-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000539243.6(ARHGAP45):c.-80C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,483,714 control chromosomes in the GnomAD database, including 28,530 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2699 hom., cov: 34)

Exomes 𝑓: 0.19 ( 25831 hom. )

Consequence

ARHGAP45
ENST00000539243.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.26

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
ARHGAP45	NM_001258328.4 link	c.-80C>T	upstream_gene_variant	NP_001245257.1	Q92619-2
ARHGAP45	XM_047438545.1 link	c.-80C>T	upstream_gene_variant	XP_047294501.1
ARHGAP45	XM_047438546.1 link	c.-1047C>T	upstream_gene_variant	XP_047294502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP45	ENST00000539243.6 link	c.-80C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	2		ENSP00000439601.1		Q92619-2
ARHGAP45	ENST00000539243.6 link	c.-80C>T		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000439601.1		Q92619-2

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25420

AN:

152150

Hom.:

2689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0438

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.190

Gnomad OTH

AF:

0.167

GnomAD4 exome

AF:

0.191

AC:

254342

AN:

1331446

Hom.:

25831

Cov.:

AF XY:

0.193

AC XY:

125786

AN XY:

651744

show subpopulations

African (AFR)

AF:

0.0339

AC:

1023

AN:

30140

American (AMR)

AF:

0.320

AC:

9442

AN:

29534

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

3757

AN:

21696

East Asian (EAS)

AF:

0.323

AC:

11418

AN:

35310

South Asian (SAS)

AF:

0.241

AC:

17244

AN:

71572

European-Finnish (FIN)

AF:

0.229

AC:

7231

AN:

31556

Middle Eastern (MID)

AF:

0.185

AC:

720

AN:

3894

European-Non Finnish (NFE)

AF:

0.183

AC:

192889

AN:

1052274

Other (OTH)

AF:

0.191

AC:

10618

AN:

55470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

10535

21069

31604

42138

52673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6966

13932

20898

27864

34830

<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:

0.167

AC:

25427

AN:

152268

Hom.:

2699

Cov.:

AF XY:

0.176

AC XY:

13090

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0437

AC:

1815

AN:

41560

American (AMR)

AF:

0.267

AC:

4083

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

583

AN:

3472

East Asian (EAS)

AF:

0.321

AC:

1663

AN:

5180

South Asian (SAS)

AF:

0.228

AC:

1102

AN:

4830

European-Finnish (FIN)

AF:

0.257

AC:

2726

AN:

10604

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.190

AC:

12895

AN:

68004

Other (OTH)

AF:

0.164

AC:

346

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1087

2174

3260

4347

5434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.170

Hom.:

4201

Bravo

AF:

0.163

Asia WGS

AF:

0.258

AC:

895

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.40

(source)

DANN

Benign

0.43

PhyloP100

-4.3

PromoterAI

-0.056

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over