13-111209940-C-G

Variant names:

• chr13-111209940-C-G
• rs368036359
• NM_001354046.2:c.406C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354046.2(ARHGEF7):​c.406C>G​(p.Leu136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L136F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARHGEF7 NM_001354046.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22374529).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354046.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF7	NM_001354046.2	MANE Select	c.406C>G	p.Leu136Val	missense	Exon 4 of 22	NP_001340975.1	A0A2R8YG42
	ARHGEF7	NM_001113511.2		c.469C>G	p.Leu157Val	missense	Exon 5 of 20	NP_001106983.1	Q14155-4
	ARHGEF7	NM_001320852.1		c.406C>G	p.Leu136Val	missense	Exon 4 of 21	NP_001307781.1	A0A8V8TQ72

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF7	ENST00000646102.2	MANE Select	c.406C>G	p.Leu136Val	missense	Exon 4 of 22	ENSP00000495631.1	A0A2R8YG42
	ARHGEF7	ENST00000375741.6	TSL:1	c.469C>G	p.Leu157Val	missense	Exon 5 of 20	ENSP00000364893.2	Q14155-4
	ARHGEF7	ENST00000317133.9	TSL:1	c.406C>G	p.Leu136Val	missense	Exon 4 of 19	ENSP00000325994.5	Q14155-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.17
Sift	Benign	0.049	D
Sift4G	Benign	0.30	T
Polyphen		0.52	P
Vest4		0.88
MutPred		0.25		Gain of MoRF binding (P = 0.0996)
MVP		0.73
MPC		1.3
ClinPred		0.47	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.44
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs368036359; hg19: chr13-111862287;