6-129578564-T-A

Position:

• chr6-129578564-T-A

Variant summary

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

The NM_033515.3(ARHGAP18):​c.1941A>T​(p.Leu647Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP18 NM_033515.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.69

Genes affected

ARHGAP18 (HGNC:21035): (Rho GTPase activating protein 18) Enables GTPase activator activity. Involved in several processes, including regulation of actin filament polymerization; regulation of small GTPase mediated signal transduction; and small GTPase mediated signal transduction. Located in cytosol; nuclear speck; and plasma membrane. Part of cytoplasmic microtubule and ruffle. Implicated in schizophrenia. [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=0.4153912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP18	NM_033515.3	c.1941A>T	p.Leu647Phe	missense_variant	15/15	ENST00000368149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP18	ENST00000368149.3	c.1941A>T	p.Leu647Phe	missense_variant	15/15	1	NM_033515.3	P1
ARHGAP18	ENST00000463225.1	n.319A>T		non_coding_transcript_exon_variant	4/4	3
ARHGAP18	ENST00000483367.5	n.315A>T		non_coding_transcript_exon_variant	4/4	3

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

Feb 28, 2024

The c.1941A>T (p.L647F) alteration is located in exon 15 (coding exon 15) of the ARHGAP18 gene. This alteration results from a A to T substitution at nucleotide position 1941, causing the leucine (L) at amino acid position 647 to be replaced by a phenylalanine (F). 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	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
REVEL	Uncertain	0.47
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.39		Loss of ubiquitination at K645 (P = 0.1037);
MVP		0.37
MPC		0.65
ClinPred		0.94	D
GERP RS		-3.0
Varity_R		0.33
gMVP		0.62

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: chr6-129899709;