chr19-1068739-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012292.5(ARHGAP45):​c.416G>C​(p.Arg139Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGAP45 NM_012292.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03877294).

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>C	p.Arg139Pro	missense	Exon 2 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.464G>C	p.Arg155Pro	missense	Exon 2 of 23	NP_001245257.1
	ARHGAP45	NM_001321232.2		c.428G>C	p.Arg143Pro	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>C	p.Arg139Pro	missense	Exon 2 of 23	ENSP00000316772.2
	ARHGAP45	ENST00000586866.5	TSL:1	c.428G>C	p.Arg143Pro	missense	Exon 2 of 23	ENSP00000468615.1
	ARHGAP45	ENST00000590214.5	TSL:5	c.497G>C	p.Arg166Pro	missense	Exon 2 of 23	ENSP00000466401.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238392 AF XY: 0.00000767

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458982 Hom.: 0 Cov.: 38 AF XY: 0.00000276 AC XY: 2 AN XY: 725586

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111012

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0040
DANN	Benign	0.76
DEOGEN2	Benign	0.036	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.075
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.33		Loss of helix (P = 0.0444)
MVP		0.040
MPC		1.0
ClinPred		0.079	T
GERP RS		-8.4
Varity_R		0.073
gMVP		0.40
Mutation Taster		=99/1	polymorphism

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;