7-144365047-C-T

Variant summary

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

The NM_005435.4(ARHGEF5):c.2378C>T(p.Ser793Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130

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=0.16333571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF5	NM_005435.4	c.2378C>T	p.Ser793Phe	missense_variant	2/15	ENST00000056217.10
ARHGEF5	XM_017012623.3	c.2378C>T	p.Ser793Phe	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.2378C>T	p.Ser793Phe	missense_variant	2/15	1	NM_005435.4	P1
ARHGEF5	ENST00000474817.5	c.140C>T	p.Ser47Phe	missense_variant	1/13	5
ARHGEF5	ENST00000498580.5	c.185-1308C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 27 AN: 134358 Hom.: 0 Cov.: 17 FAILED QC

Gnomad AFR AF: 0.0000840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000358

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000192 AC: 182 AN: 950092 Hom.: 0 Cov.: 13 AF XY: 0.000193 AC XY: 92 AN XY: 477576

Gnomad4 AFR exome AF: 0.0000892

Gnomad4 AMR exome AF: 0.0000610

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000659

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.0000697

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000201 AC: 27 AN: 134474 Hom.: 0 Cov.: 17 AF XY: 0.000154 AC XY: 10 AN XY: 64900

Gnomad4 AFR AF: 0.0000837

Gnomad4 AMR AF: 0.0000738

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000112

Gnomad4 NFE AF: 0.000358

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000239 AC: 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 12, 2022

The c.2378C>T (p.S793F) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a C to T substitution at nucleotide position 2378, causing the serine (S) at amino acid position 793 to be replaced by a phenylalanine (F). 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	0.23
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.23
MutPred		0.16		Loss of glycosylation at S793 (P = 0.0018);
MVP		0.51
ClinPred		0.16	T
GERP RS		3.3
Varity_R		0.20
gMVP		0.17

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: rs772010530; hg19: chr7-144062140;