18-6887171-A-G

Position:

• chr18-6887171-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366230.1(ARHGAP28):​c.1468A>G​(p.Lys490Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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: ARHGAP28 NM_001366230.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

Genes affected

ARHGAP28 (HGNC:25509): (Rho GTPase activating protein 28) Predicted to enable GTPase activator activity. Predicted to be involved in negative regulation of GTP binding activity; regulation of actin filament organization; and regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30095035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP28	NM_001366230.1	c.1468A>G	p.Lys490Glu	missense_variant	12/18	ENST00000383472.9	NP_001353159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP28	ENST00000383472.9	c.1468A>G	p.Lys490Glu	missense_variant	12/18	5	NM_001366230.1	ENSP00000372964	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 24, 2022

The c.991A>G (p.K331E) alteration is located in exon 11 (coding exon 10) of the ARHGAP28 gene. This alteration results from a A to G substitution at nucleotide position 991, causing the lysine (K) at amino acid position 331 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;.;T;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.
MutationTaster	Benign	0.61	D;D;D;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	.;D;D;D;D;.;.
REVEL	Benign	0.075
Sift	Uncertain	0.0020	.;D;D;D;D;.;.
Sift4G	Uncertain	0.0080	D;T;D;D;D;T;T
Polyphen		0.078	B;B;.;.;.;.;.
Vest4		0.46
MutPred		0.35		Loss of ubiquitination at K490 (P = 0.021);.;.;.;.;.;.;
MVP		0.30
MPC		0.35
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-6887170;