Genetic Variant ARHGEF7:p.Ser223Arg (chr13-111217879-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001354046.2(ARHGEF7):c.669C>A(p.Ser223Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S223S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ARHGEF7
NM_001354046.2 missense, splice_region

Scores

Splicing: ADA: 0.00001662

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.654

Publications

0 publications found

Variant links:

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]

ARHGEF7 links:

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ACMG classification

Classification was made for transcript

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=0.2106612).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF7	NM_001354046.2	MANE Select	c.669C>A	p.Ser223Arg	missense splice_region	Exon 5 of 22	NP_001340975.1	A0A2R8YG42
ARHGEF7	NM_001113511.2		c.732C>A	p.Ser244Arg	missense splice_region	Exon 6 of 20	NP_001106983.1	Q14155-4
ARHGEF7	NM_001320852.1		c.669C>A	p.Ser223Arg	missense splice_region	Exon 5 of 21	NP_001307781.1	A0A8V8TQ72

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF7	ENST00000646102.2	MANE Select	c.669C>A	p.Ser223Arg	missense splice_region	Exon 5 of 22	ENSP00000495631.1	A0A2R8YG42
ARHGEF7	ENST00000375741.6	TSL:1	c.732C>A	p.Ser244Arg	missense splice_region	Exon 6 of 20	ENSP00000364893.2	Q14155-4
ARHGEF7	ENST00000317133.9	TSL:1	c.669C>A	p.Ser223Arg	missense splice_region	Exon 5 of 19	ENSP00000325994.5	Q14155-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456472

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108054

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

2.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.016

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.96

MutationAssessor

Benign

2.0

PhyloP100

-0.65

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.11

Sift

Uncertain

0.021

Sift4G

Benign

0.094

Polyphen

0.40

Vest4

0.27

MutPred

0.35

Loss of glycosylation at S244 (P = 0.0238)

MVP

0.50

MPC

0.69

ClinPred

0.80

GERP RS

-7.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.28

gMVP

0.43

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.092

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over