17-45397011-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282290.2(ARHGAP27):c.1856C>T(p.Pro619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGAP27 NM_001282290.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.781

Genes affected

ARHGAP27 (HGNC:31813): (Rho GTPase activating protein 27) This gene encodes a member of a large family of proteins that activate Rho-type guanosine triphosphate (GTP) metabolizing enzymes. The encoded protein may pay a role in clathrin-mediated endocytosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2013]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10776734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP27	NM_001282290.2	c.1856C>T	p.Pro619Leu	missense_variant	14/20	ENST00000685559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP27	ENST00000685559.1	c.1856C>T	p.Pro619Leu	missense_variant	14/20		NM_001282290.2
	ENST00000592389.1	n.80G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451226 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 07, 2022

The c.833C>T (p.P278L) alteration is located in exon 11 (coding exon 10) of the ARHGAP27 gene. This alteration results from a C to T substitution at nucleotide position 833, causing the proline (P) at amino acid position 278 to be replaced by a leucine (L). 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	0.078
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Benign	0.79
DEOGEN2	Benign	0.024	T;T;.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T;T;T;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.0010	.;B;.;.;.
Vest4		0.20
MutPred		0.23		.;Loss of glycosylation at P619 (P = 0.0095);.;.;.;
MVP		0.44
MPC		0.40
ClinPred		0.18	T
GERP RS		2.5
Varity_R		0.044
gMVP		0.25

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: chr17-43474377;