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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF1	NM_004706.4 link	c.225+350A>G		intron_variant	Intron 4 of 28	ENST00000354532.8	NP_004697.2	Q92888-1A0A024R0R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF1	ENST00000354532.8 link	c.225+350A>G		intron_variant	Intron 4 of 28	1	NM_004706.4	ENSP00000346532.3		Q92888-1

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 v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over