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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP45	NM_012292.5	c.416G>A	p.Arg139His	missense_variant	Exon 2 of 23	ENST00000313093.7	NP_036424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP45	ENST00000313093.7	c.416G>A	p.Arg139His	missense_variant	Exon 2 of 23	1	NM_012292.5	ENSP00000316772.2

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

Gnomad4 AFR exome AF: 0.516 AC: 17252 AN: 33402

Gnomad4 AMR exome AF: 0.421 AC: 18784 AN: 44630

Gnomad4 ASJ exome AF: 0.316 AC: 8238 AN: 26100

Gnomad4 EAS exome AF: 0.355 AC: 14088 AN: 39636

Gnomad4 SAS exome AF: 0.386 AC: 33261 AN: 86174

Gnomad4 FIN exome AF: 0.360 AC: 18707 AN: 51892

Gnomad4 NFE exome AF: 0.362 AC: 401390 AN: 1110246

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.523 AC: 0.523254 AN: 0.523254

Gnomad4 AMR AF: 0.413 AC: 0.413024 AN: 0.413024

Gnomad4 ASJ AF: 0.314 AC: 0.314269 AN: 0.314269

Gnomad4 EAS AF: 0.348 AC: 0.348426 AN: 0.348426

Gnomad4 SAS AF: 0.365 AC: 0.364826 AN: 0.364826

Gnomad4 FIN AF: 0.368 AC: 0.368211 AN: 0.368211

Gnomad4 NFE AF: 0.363 AC: 0.362664 AN: 0.362664

Gnomad4 OTH AF: 0.385 AC: 0.385199 AN: 0.385199

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 v4.3

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;T;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.33	T;T;T;T;T
MetaRNN	Benign	0.000023	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.75	.;.;N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.39	N;.;N;.;.
REVEL	Benign	0.10
Sift	Benign	0.27	T;.;T;.;.
Sift4G	Benign	0.17	T;T;T;T;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

Publications

LitVar

Other links and lift over

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