17-45396739-C-T

Position:

• chr17-45396739-C-T

Variant summary

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

The NM_001282290.2(ARHGAP27):​c.2003G>A​(p.Arg668Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGAP27 NM_001282290.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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]

ARHGAP27 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP27	NM_001282290.2	c.2003G>A	p.Arg668Gln	missense_variant	15/20	ENST00000685559.1	NP_001269219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP27	ENST00000685559.1	c.2003G>A	p.Arg668Gln	missense_variant	15/20		NM_001282290.2	ENSP00000509127.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461468 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

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: 0.00000180

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 04, 2024

The c.980G>A (p.R327Q) alteration is located in exon 12 (coding exon 11) of the ARHGAP27 gene. This alteration results from a G to A substitution at nucleotide position 980, causing the arginine (R) at amino acid position 327 to be replaced by a glutamine (Q). 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	0.26
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.032	T;T;.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.59
MutPred		0.46		.;Gain of ubiquitination at K666 (P = 0.0371);.;.;.;
MVP		0.53
MPC		1.1
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.29
gMVP		0.68

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: chr17-43474105; COSMIC: COSV100976467; COSMIC: COSV100976467;