18-6837370-T-C

Position:

• chr18-6837370-T-C

Variant summary

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

The NM_001366230.1(ARHGAP28):​c.499T>C​(p.Ser167Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARHGAP28 NM_001366230.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.637

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 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=0.022560507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP28	NM_001366230.1	c.499T>C	p.Ser167Pro	missense_variant	3/18	ENST00000383472.9	NP_001353159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP28	ENST00000383472.9	c.499T>C	p.Ser167Pro	missense_variant	3/18	5	NM_001366230.1	ENSP00000372964.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Nov 08, 2024

The c.22T>C (p.S8P) alteration is located in exon 2 (coding exon 1) of the ARHGAP28 gene. This alteration results from a T to C substitution at nucleotide position 22, causing the serine (S) at amino acid position 8 to be replaced by a proline (P). 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	0.057
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.64
DANN	Benign	0.76
DEOGEN2	Benign	0.0065	T;T;T;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.72	T;T;T;T;T;.;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N;.;.;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.9	.;.;N;N;.;N;N;N
REVEL	Benign	0.055
Sift	Benign	1.0	.;.;T;T;.;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;.;.;.
Vest4		0.071
MutPred		0.17		.;.;.;.;Loss of phosphorylation at S8 (P = 0.0047);Loss of phosphorylation at S8 (P = 0.0047);Loss of phosphorylation at S8 (P = 0.0047);Loss of phosphorylation at S8 (P = 0.0047);
MVP		0.048
MPC		0.21
ClinPred		0.053	T
GERP RS		-0.92
Varity_R		0.061
gMVP		0.028

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-6837369;