chr7-144364173-G-T

Position:

• chr7-144364173-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_005435.4(ARHGEF5):​c.1504G>T​(p.Val502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 3)
  • Exomes 𝑓: 0.00080 (133 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.694

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 -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ARHGEF5
• BP4: Computational evidence support a benign effect (MetaRNN=0.015350014).
• BP6: Variant 7-144364173-G-T is Benign according to our data. Variant chr7-144364173-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2658128.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF5	NM_005435.4	c.1504G>T	p.Val502Leu	missense_variant	2/15	ENST00000056217.10
ARHGEF5	XM_017012623.3	c.1504G>T	p.Val502Leu	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.1504G>T	p.Val502Leu	missense_variant	2/15	1	NM_005435.4	P1
ARHGEF5	ENST00000498580.5	c.184+1320G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12 AN: 49410 Hom.: 0 Cov.: 3 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000555

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000693 AC: 80 AN: 115512 Hom.: 32 AF XY: 0.000694 AC XY: 43 AN XY: 61980

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000211

Gnomad SAS exome AF: 0.000310

Gnomad FIN exome AF: 0.000872

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000795 AC: 558 AN: 701540 Hom.: 133 Cov.: 8 AF XY: 0.000806 AC XY: 286 AN XY: 355050

Gnomad4 AFR exome AF: 0.000106

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000384

Gnomad4 SAS exome AF: 0.000840

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000919

Gnomad4 OTH exome AF: 0.000419

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000243 AC: 12 AN: 49438 Hom.: 0 Cov.: 3 AF XY: 0.000208 AC XY: 5 AN XY: 24084

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000555

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000298 Hom.: 0

ExAC AF: 0.000939 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1504G>T (p.V502L) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a G to T substitution at nucleotide position 1504, causing the valine (V) at amino acid position 502 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ARHGEF5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.33
DANN	Benign	0.70
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.097
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.23		Loss of sheet (P = 0.0817);
MVP		0.48
ClinPred		0.0020	T
GERP RS		-8.0
Varity_R		0.047
gMVP		0.074

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: rs752820457; hg19: chr7-144061266;