7-144364099-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_005435.4(ARHGEF5):c.1430A>G(p.Lys477Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 5)
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.119

Genes affected

ARHGEF5 (HGNC:13209): (Rho guanine nucleotide exchange factor 5) Rho GTPases play a fundamental role in numerous cellular processes initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein may be involved in the control of cytoskeletal organization. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ARHGEF5
• BP4: Computational evidence support a benign effect (MetaRNN=0.078988194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF5	NM_005435.4	c.1430A>G	p.Lys477Arg	missense_variant	2/15	ENST00000056217.10
ARHGEF5	XM_017012623.3	c.1430A>G	p.Lys477Arg	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.1430A>G	p.Lys477Arg	missense_variant	2/15	1	NM_005435.4	P1
ARHGEF5	ENST00000498580.5	c.184+1246A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Cov.: 13

GnomAD4 genome Cov.: 5

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

Jan 17, 2023

The c.1430A>G (p.K477R) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a A to G substitution at nucleotide position 1430, causing the lysine (K) at amino acid position 477 to be replaced by an arginine (R). 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	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.8
Dann	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.060
Sift	Uncertain	0.012	D
Sift4G	Benign	0.14	T
Polyphen		0.14	B
Vest4		0.052
MutPred		0.25		Loss of ubiquitination at K477 (P = 4e-04);
MVP		0.65
ClinPred		0.077	T
GERP RS		1.0
Varity_R		0.072
gMVP		0.050

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: chr7-144061192;