chr19-1068739-G-A

Variant names:

• chr19-1068739-G-A
• rs1801284
• NM_012292.5:c.416G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012292.5(ARHGAP45):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,609,774 control chromosomes in the GnomAD database, including 113,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13117 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99911 hom.)
• Consequence: ARHGAP45 NM_012292.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 37 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.250445E-5).
• BP6: Variant 19-1068739-G-A is Benign according to our data. Variant chr19-1068739-G-A is described in ClinVar as Benign. ClinVar VariationId is 1225485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	NM_012292.5	MANE Select	c.416G>A	p.Arg139His	missense	Exon 2 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.464G>A	p.Arg155His	missense	Exon 2 of 23	NP_001245257.1
	ARHGAP45	NM_001321232.2		c.428G>A	p.Arg143His	missense	Exon 2 of 23	NP_001308161.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.416G>A	p.Arg139His	missense	Exon 2 of 23	ENSP00000316772.2
	ARHGAP45	ENST00000586866.5	TSL:1	c.428G>A	p.Arg143His	missense	Exon 2 of 23	ENSP00000468615.1
	ARHGAP45	ENST00000590214.5	TSL:5	c.497G>A	p.Arg166His	missense	Exon 2 of 23	ENSP00000466401.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62149 AN: 151518 Hom.: 13084 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.379 AC: 90238 AN: 238392 AF XY: 0.376

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.368 AC: 535921 AN: 1458138 Hom.: 99911 Cov.: 38 AF XY: 0.368 AC XY: 266553 AN XY: 725198

African (AFR) AF: 0.516 AC: 17252 AN: 33402

American (AMR) AF: 0.421 AC: 18784 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8238 AN: 26100

East Asian (EAS) AF: 0.355 AC: 14088 AN: 39636

South Asian (SAS) AF: 0.386 AC: 33261 AN: 86174

European-Finnish (FIN) AF: 0.360 AC: 18707 AN: 51892

Middle Eastern (MID) AF: 0.336 AC: 1933 AN: 5760

European-Non Finnish (NFE) AF: 0.362 AC: 401390 AN: 1110246

Other (OTH) AF: 0.369 AC: 22268 AN: 60298

GnomAD4 genome AF: 0.410 AC: 62228 AN: 151636 Hom.: 13117 Cov.: 32 AF XY: 0.411 AC XY: 30468 AN XY: 74082

African (AFR) AF: 0.523 AC: 21602 AN: 41284

American (AMR) AF: 0.413 AC: 6292 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3462

East Asian (EAS) AF: 0.348 AC: 1793 AN: 5146

South Asian (SAS) AF: 0.365 AC: 1757 AN: 4816

European-Finnish (FIN) AF: 0.368 AC: 3878 AN: 10532

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24606 AN: 67848

Other (OTH) AF: 0.385 AC: 812 AN: 2108

Alfa AF: 0.380 Hom.: 33720

Bravo AF: 0.420

TwinsUK AF: 0.345 AC: 1278

ALSPAC AF: 0.362 AC: 1396

ESP6500AA AF: 0.510 AC: 2239

ESP6500EA AF: 0.351 AC: 3014

ExAC AF: 0.377 AC: 45282

Asia WGS AF: 0.351 AC: 1218 AN: 3478

EpiCase AF: 0.363

EpiControl AF: 0.356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9461441, 15593299)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0040
DANN	Benign	0.92
DEOGEN2	Benign	0.021	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.000023	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.75	N
PhyloP100		-1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.10
Sift	Benign	0.27	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.060
MPC		0.89
ClinPred		0.012	T
GERP RS		-8.4
Varity_R		0.019
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1801284; hg19: chr19-1068738; COSMIC: COSV54033850; COSMIC: COSV54033850;