19-1080114-G-A

Position:

• chr19-1080114-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012292.5(ARHGAP45):​c.1699G>A​(p.Ala567Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP45 NM_012292.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.851

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0396083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP45	NM_012292.5	c.1699G>A	p.Ala567Thr	missense_variant	13/23	ENST00000313093.7	NP_036424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP45	ENST00000313093.7	c.1699G>A	p.Ala567Thr	missense_variant	13/23	1	NM_012292.5	ENSP00000316772	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.1699G>A (p.A567T) alteration is located in exon 13 (coding exon 13) of the ARHGAP45 gene. This alteration results from a G to A substitution at nucleotide position 1699, causing the alanine (A) at amino acid position 567 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.056
DANN	Benign	0.67
DEOGEN2	Benign	0.0065	.;T;.;.;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.040	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	.;L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.10	N;N;.;.;N;.
REVEL	Benign	0.0090
Sift	Benign	0.55	T;T;.;.;T;.
Sift4G	Benign	0.77	T;T;T;T;T;T
Polyphen		0.0090, 0.065	.;B;.;.;B;.
Vest4		0.090
MutPred		0.32		.;Gain of relative solvent accessibility (P = 0.0166);.;.;.;.;
MVP		0.014
MPC		0.70
ClinPred		0.052	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.47

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: rs2043386726; hg19: chr19-1080113;