7-144362925-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_005435.4(ARHGEF5):c.256G>A(p.Val86Met) 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. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.213

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ARHGEF5
• BP4: Computational evidence support a benign effect (MetaRNN=0.06704295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF5	NM_005435.4	c.256G>A	p.Val86Met	missense_variant	2/15	ENST00000056217.10
ARHGEF5	XM_017012623.3	c.256G>A	p.Val86Met	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.256G>A	p.Val86Met	missense_variant	2/15	1	NM_005435.4	P1
ARHGEF5	ENST00000498580.5	c.184+72G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000179 AC: 2 AN: 1115650 Hom.: 0 Cov.: 18 AF XY: 0.00000179 AC XY: 1 AN XY: 559844

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: 0.0000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

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

Jun 07, 2023

The c.256G>A (p.V86M) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a G to A substitution at nucleotide position 256, causing the valine (V) at amino acid position 86 to be replaced by a methionine (M). 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	0.094
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.7
Dann	Benign	0.79
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.13
Sift	Benign	0.47	T
Sift4G	Benign	0.20	T
Polyphen		0.24	B
Vest4		0.046
MutPred		0.096		Loss of glycosylation at S83 (P = 0.1944);
MVP		0.36
ClinPred		0.053	T
GERP RS		-0.65
Varity_R		0.022
gMVP		0.045

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: rs2053653117; hg19: chr7-144060018;