dbSNP rs717225: ARHGEF1:c.225+350A>G (chr19-41889215-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004706.4(ARHGEF1):c.225+350A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 213,628 control chromosomes in the GnomAD database, including 11,544 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 10727 hom., cov: 32)

Exomes 𝑓: 0.063 ( 817 hom. )

Consequence

ARHGEF1
NM_004706.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.940

Publications

12 publications found

Variant links:

Genes affected

ARHGEF1 (HGNC:681): (Rho guanine nucleotide exchange factor 1) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ARHGEF1 Gene-Disease associations (from GenCC):

immunodeficiency 62
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ARHGEF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004706.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF1	NM_004706.4	MANE Select	c.225+350A>G	intron	N/A	NP_004697.2
ARHGEF1	NM_001396000.1		c.225+350A>G	intron	N/A	NP_001382929.1	M0QZR4
ARHGEF1	NM_001396006.1		c.225+350A>G	intron	N/A	NP_001382935.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF1	ENST00000354532.8	TSL:1 MANE Select	c.225+350A>G	intron	N/A	ENSP00000346532.3	Q92888-1
ARHGEF1	ENST00000378152.8	TSL:1	c.270+350A>G	intron	N/A	ENSP00000367394.3	Q92888-4
ARHGEF1	ENST00000337665.8	TSL:1	c.270+350A>G	intron	N/A	ENSP00000337261.3	Q92888-3

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33732

AN:

152010

Hom.:

10688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0863

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.0542

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.00637

Gnomad OTH

AF:

0.168

GnomAD4 exome

AF:

0.0632

AC:

3885

AN:

61500

Hom.:

817

Cov.:

AF XY:

0.0603

AC XY:

1929

AN XY:

32012

show subpopulations

African (AFR)

AF:

0.710

AC:

1867

AN:

2630

American (AMR)

AF:

0.0568

AC:

207

AN:

3646

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

104

AN:

2214

East Asian (EAS)

AF:

0.161

AC:

689

AN:

4276

South Asian (SAS)

AF:

0.0971

AC:

428

AN:

4408

European-Finnish (FIN)

AF:

0.0427

AC:

104

AN:

2434

Middle Eastern (MID)

AF:

0.0483

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00473

AC:

179

AN:

37832

Other (OTH)

AF:

0.0777

AC:

293

AN:

3770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

113

226

338

451

564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.222

AC:

33832

AN:

152128

Hom.:

10727

Cov.:

AF XY:

0.221

AC XY:

16433

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.703

AC:

29145

AN:

41454

American (AMR)

AF:

0.0862

AC:

1318

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3470

East Asian (EAS)

AF:

0.213

AC:

1100

AN:

5174

South Asian (SAS)

AF:

0.141

AC:

682

AN:

4824

European-Finnish (FIN)

AF:

0.0542

AC:

575

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00635

AC:

432

AN:

67986

Other (OTH)

AF:

0.174

AC:

367

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

632

1264

1895

2527

3159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.0578

Hom.:

6525

Bravo

AF:

0.246

Asia WGS

AF:

0.264

AC:

918

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.0

(source)

DANN

Benign

0.69

PhyloP100

-0.94

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over