7-144364782-C-A

Variant summary

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

The NM_005435.4(ARHGEF5):c.2113C>A(p.Pro705Thr) 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: 2)
  • Exomes 𝑓: 0.0000078 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

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=0.08257571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF5	NM_005435.4	c.2113C>A	p.Pro705Thr	missense_variant	2/15	ENST00000056217.10
ARHGEF5	XM_017012623.3	c.2113C>A	p.Pro705Thr	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.2113C>A	p.Pro705Thr	missense_variant	2/15	1	NM_005435.4	P1
ARHGEF5	ENST00000498580.5	c.185-1573C>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000783 AC: 3 AN: 383326 Hom.: 0 Cov.: 0 AF XY: 0.00000997 AC XY: 2 AN XY: 200670

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: 0.0000133

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 2

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

Oct 26, 2022

The c.2113C>A (p.P705T) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a C to A substitution at nucleotide position 2113, causing the proline (P) at amino acid position 705 to be replaced by a threonine (T). 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	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	11
Dann	Benign	0.87
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.056
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.26	T
Polyphen		0.0080	B
Vest4		0.088
MutPred		0.17		Gain of catalytic residue at P705 (P = 0.0093);
MVP		0.11
ClinPred		0.15	T
GERP RS		0.76
Varity_R		0.098
gMVP		0.20

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: chr7-144061875;