chr13-111205352-A-G

Position:

• chr13-111205352-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354046.2(ARHGEF7):​c.316A>G​(p.Thr106Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF7 NM_001354046.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

Genes affected

ARHGEF7 (HGNC:15607): (Rho guanine nucleotide exchange factor 7) This gene encodes a protein that belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It forms a complex with the small GTP binding protein Rac1 and recruits Rac1 to membrane ruffles and to focal adhesions. Multiple alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083029926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF7	NM_001354046.2	c.316A>G	p.Thr106Ala	missense_variant	3/22	ENST00000646102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF7	ENST00000646102.2	c.316A>G	p.Thr106Ala	missense_variant	3/22		NM_001354046.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

May 08, 2024

The c.379A>G (p.T127A) alteration is located in exon 4 (coding exon 4) of the ARHGEF7 gene. This alteration results from a A to G substitution at nucleotide position 379, causing the threonine (T) at amino acid position 127 to be replaced by an alanine (A). 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	0.066
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.25
DEOGEN2	Benign	0.15	.;.;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-2.1	.;.;N;.;.
MutationTaster	Benign	0.55	D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.92	N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;.;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.084
MutPred		0.69		.;.;Gain of ubiquitination at K130 (P = 0.0913);.;.;
MVP		0.69
MPC		0.57
ClinPred		0.46	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.30

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: rs1333036825; hg19: chr13-111857699;