7-144363511-A-G

Position:

• chr7-144363511-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005435.4(ARHGEF5):​c.842A>G​(p.Asp281Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 26)
• Consequence: ARHGEF5 NM_005435.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.408

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0525198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF5	NM_005435.4	c.842A>G	p.Asp281Gly	missense_variant	2/15	ENST00000056217.10	NP_005426.2
ARHGEF5	XM_017012623.3	c.842A>G	p.Asp281Gly	missense_variant	2/6		XP_016868112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF5	ENST00000056217.10	c.842A>G	p.Asp281Gly	missense_variant	2/15	1	NM_005435.4	ENSP00000056217.5
ARHGEF5	ENST00000498580.5	c.184+658A>G		intron_variant		3		ENSP00000417979.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

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

Aug 20, 2024

The c.842A>G (p.D281G) 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 842, causing the aspartic acid (D) at amino acid position 281 to be replaced by a glycine (G). 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	0.090
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.84
DANN	Benign	0.93
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Benign	0.076	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.27		Gain of sheet (P = 0.0028);
MVP		0.35
ClinPred		0.081	T
GERP RS		-4.6
Varity_R		0.080
gMVP		0.11

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: chr7-144060604;