17-45395478-G-A

Variant names:

• chr17-45395478-G-A
• rs148792420
• NM_001282290.2:c.2648C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001282290.2(ARHGAP27):​c.2648C>T​(p.Ala883Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,568,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ARHGAP27 NM_001282290.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012204975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP27	NM_001282290.2	c.2648C>T	p.Ala883Val	missense_variant	Exon 20 of 20	ENST00000685559.1	NP_001269219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP27	ENST00000685559.1	c.2648C>T	p.Ala883Val	missense_variant	Exon 20 of 20		NM_001282290.2	ENSP00000509127.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000211 AC: 38 AN: 180010 AF XY: 0.000228

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.000287

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000636

GnomAD4 exome AF: 0.000141 AC: 200 AN: 1416642 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 101 AN XY: 700780

African (AFR) AF: 0.000462 AC: 15 AN: 32492

American (AMR) AF: 0.000283 AC: 11 AN: 38816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 37046

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49608

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5706

European-Non Finnish (NFE) AF: 0.000130 AC: 142 AN: 1088176

Other (OTH) AF: 0.000290 AC: 17 AN: 58596

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74494

African (AFR) AF: 0.000529 AC: 22 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000458 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000176 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1625C>T (p.A542V) alteration is located in exon 17 (coding exon 16) of the ARHGAP27 gene. This alteration results from a C to T substitution at nucleotide position 1625, causing the alanine (A) at amino acid position 542 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	.;N;.;.;.
PhyloP100		2.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.096	T;D;D;T;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.26	.;B;.;.;.
Vest4		0.13
MVP		0.32
MPC		0.40
ClinPred		0.0098	T
GERP RS		3.4
Varity_R		0.058
gMVP		0.081
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs148792420; hg19: chr17-43472844;