14-32090813-A-T

Position:

• chr14-32090813-A-T

Variant summary

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

The NM_001030055.2(ARHGAP5):​c.144A>T​(p.Glu48Asp) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP5 NM_001030055.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.671

Genes affected

ARHGAP5 (HGNC:675): (Rho GTPase activating protein 5) Rho GTPase activating protein 5 negatively regulates RHO GTPases, a family which may mediate cytoskeleton changes by stimulating the hydrolysis of bound GTP. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.07770431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP5	NM_001030055.2	c.144A>T	p.Glu48Asp	missense_variant	2/7	ENST00000345122.8	NP_001025226.1
ARHGAP5	NM_001173.3	c.144A>T	p.Glu48Asp	missense_variant	2/7		NP_001164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP5	ENST00000345122.8	c.144A>T	p.Glu48Asp	missense_variant	2/7	5	NM_001030055.2	ENSP00000371897	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 24, 2023

The c.144A>T (p.E48D) alteration is located in exon 2 (coding exon 1) of the ARHGAP5 gene. This alteration results from a A to T substitution at nucleotide position 144, causing the glutamic acid (E) at amino acid position 48 to be replaced by an aspartic acid (D). 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	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.43
DEOGEN2	Benign	0.10	.;T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T;.;T;T;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.81	N;N;.;N;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	2.3	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.20
MutPred		0.48		Loss of methylation at K45 (P = 0.0696);Loss of methylation at K45 (P = 0.0696);Loss of methylation at K45 (P = 0.0696);Loss of methylation at K45 (P = 0.0696);Loss of methylation at K45 (P = 0.0696);
MVP		0.52
MPC		0.23
ClinPred		0.046	T
GERP RS		1.9
Varity_R		0.030
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs1878203406; hg19: chr14-32560019;