Genetic Variant NM_001354046.2:c.146T>G (chr13-111115672-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001354046.2(ARHGEF7):c.146T>G(p.Leu49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,279,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ARHGEF7
NM_001354046.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94

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:

ARHGEF7-AS2 (HGNC:40717): (ARHGEF7 antisense RNA 2)

ARHGEF7-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29176027).

BS2

High AC in GnomAdExome4 at 13 AD gene.

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.146T>G	p.Leu49Arg	missense	Exon 1 of 22	NP_001340975.1	A0A2R8YG42
ARHGEF7	NM_001113511.2		c.146T>G	p.Leu49Arg	missense	Exon 1 of 20	NP_001106983.1	Q14155-4
ARHGEF7	NM_001320852.1		c.146T>G	p.Leu49Arg	missense	Exon 1 of 21	NP_001307781.1	A0A8V8TQ72

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF7	ENST00000646102.2	MANE Select	c.146T>G	p.Leu49Arg	missense	Exon 1 of 22	ENSP00000495631.1	A0A2R8YG42
ARHGEF7	ENST00000375741.6	TSL:1	c.146T>G	p.Leu49Arg	missense	Exon 1 of 20	ENSP00000364893.2	Q14155-4
ARHGEF7	ENST00000317133.9	TSL:1	c.146T>G	p.Leu49Arg	missense	Exon 1 of 19	ENSP00000325994.5	Q14155-3

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

147786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000451

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000844

AC:

AN:

118546

AF XY:

0.0000145

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1131920

Hom.:

Cov.:

AF XY:

0.0000162

AC XY:

AN XY:

554612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22196

American (AMR)

AF:

0.00

AC:

AN:

16292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14894

East Asian (EAS)

AF:

0.00

AC:

AN:

24320

South Asian (SAS)

AF:

0.00

AC:

AN:

42858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

938940

Other (OTH)

AF:

0.00

AC:

AN:

42276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

AF:

0.0000271

AC:

AN:

147786

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71994

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40578

American (AMR)

AF:

0.00

AC:

AN:

14946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4974

South Asian (SAS)

AF:

0.00

AC:

AN:

4708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

66530

Other (OTH)

AF:

0.00

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-0.51

PhyloP100

2.9

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.68

REVEL

Benign

0.23

Sift

Benign

0.22

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.15

MVP

0.60

MPC

0.88

ClinPred

0.11

GERP RS

1.8

PromoterAI

0.040

Neutral

(source)

Varity_R

0.32

gMVP

0.20

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over