19-1077935-C-T

Variant names:

• chr19-1077935-C-T
• rs1174064437
• NM_012292.5:c.1264C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012292.5(ARHGAP45):​c.1264C>T​(p.Leu422Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,553,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ARHGAP45 NM_012292.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.972
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10786095).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	NM_012292.5	MANE Select	c.1264C>T	p.Leu422Phe	missense	Exon 11 of 23	NP_036424.2
	ARHGAP45	NM_001258328.4		c.1312C>T	p.Leu438Phe	missense	Exon 11 of 23	NP_001245257.1	Q92619-2
	ARHGAP45	NM_001321232.2		c.1276C>T	p.Leu426Phe	missense	Exon 11 of 23	NP_001308161.1	K7ES98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.1264C>T	p.Leu422Phe	missense	Exon 11 of 23	ENSP00000316772.2	Q92619-1
	ARHGAP45	ENST00000586866.5	TSL:1	c.1276C>T	p.Leu426Phe	missense	Exon 11 of 23	ENSP00000468615.1	K7ES98
	ARHGAP45	ENST00000885660.1		c.1264C>T	p.Leu422Phe	missense	Exon 11 of 22	ENSP00000555719.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000629 AC: 1 AN: 158974 AF XY: 0.00

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: 0.0000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1401430 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691444

African (AFR) AF: 0.00 AC: 0 AN: 31708

American (AMR) AF: 0.00 AC: 0 AN: 35888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36040

South Asian (SAS) AF: 0.00 AC: 0 AN: 79404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1080090

Other (OTH) AF: 0.00 AC: 0 AN: 58092

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.97
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.039
Sift	Benign	0.42	T
Sift4G	Benign	0.51	T
Polyphen		0.80	P
Vest4		0.099
MutPred		0.29		Gain of methylation at K425 (P = 0.0792)
MVP		0.27
MPC		1.4
ClinPred		0.72	D
GERP RS		3.8
PromoterAI		-0.018	Neutral
Varity_R		0.13
gMVP		0.32
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1174064437; hg19: chr19-1077934;