13-111205290-C-G

Variant names:

• chr13-111205290-C-G
• rs768494805
• NM_001354046.2:c.254C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001354046.2(ARHGEF7):​c.254C>G​(p.Thr85Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000691 in 1,447,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. T85M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF7 NM_001354046.2 missense, splice_region
• Scores: Splicing: ADA: 0.9869
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.254C>G	p.Thr85Arg	missense splice_region	Exon 3 of 22	NP_001340975.1	A0A2R8YG42
	ARHGEF7	NM_001113511.2		c.317C>G	p.Thr106Arg	missense splice_region	Exon 4 of 20	NP_001106983.1	Q14155-4
	ARHGEF7	NM_001320852.1		c.254C>G	p.Thr85Arg	missense splice_region	Exon 3 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.254C>G	p.Thr85Arg	missense splice_region	Exon 3 of 22	ENSP00000495631.1	A0A2R8YG42
	ARHGEF7	ENST00000375741.6	TSL:1	c.317C>G	p.Thr106Arg	missense splice_region	Exon 4 of 20	ENSP00000364893.2	Q14155-4
	ARHGEF7	ENST00000317133.9	TSL:1	c.254C>G	p.Thr85Arg	missense splice_region	Exon 3 of 19	ENSP00000325994.5	Q14155-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447096 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719828

African (AFR) AF: 0.00 AC: 0 AN: 32304

American (AMR) AF: 0.00 AC: 0 AN: 39726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 82998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108422

Other (OTH) AF: 0.00 AC: 0 AN: 59770

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Benign	0.090	T
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.63
MutPred		0.53		Loss of loop (P = 0.1242)
MVP		0.86
MPC		1.6
ClinPred		0.75	D
GERP RS		5.7
PromoterAI		-0.016	Neutral
Varity_R		0.17
gMVP		0.62
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.16		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: rs768494805; hg19: chr13-111857637;