Genetic Variant NM_001367823.1:c.968-359T>A (chr19-7439985-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001367823.1(ARHGEF18):c.968-359T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,547,440 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00090 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 4 hom. )

Consequence

ARHGEF18
NM_001367823.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0960

Publications

0 publications found

Variant links:

Genes affected

ARHGEF18 (HGNC:17090): (Rho/Rac guanine nucleotide exchange factor 18) Rho GTPases are GTP binding proteins that regulate a wide spectrum of cellular functions. These cellular processes include cytoskeletal rearrangements, gene transcription, cell growth and motility. Activation of Rho GTPases is under the direct control of guanine nucleotide exchange factors (GEFs). The protein encoded by this gene is a guanine nucleotide exchange factor and belongs to the Rho GTPase GEF family. Family members share a common feature, a Dbl (DH) homology domain followed by a pleckstrin (PH) homology domain. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2018]

ARHGEF18 Gene-Disease associations (from GenCC):

retinitis pigmentosa 78
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
inherited retinal dystrophy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARHGEF18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-7439985-T-A is Benign according to our data. Variant chr19-7439985-T-A is described in ClinVar as Benign. ClinVar VariationId is 715866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0009 (137/152156) while in subpopulation NFE AF = 0.000912 (62/67978). AF 95% confidence interval is 0.00073. There are 2 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367823.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF18	NM_001367823.1	MANE Select	c.968-359T>A	intron	N/A	NP_001354752.1	Q6ZSZ5-4
ARHGEF18	NM_001130955.2		c.-118T>A	5_prime_UTR	Exon 1 of 20	NP_001124427.2	A0A3B3IPE9
ARHGEF18	NM_001367824.1		c.-226-204T>A	intron	N/A	NP_001354753.1	Q6ZSZ5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF18	ENST00000668164.2	MANE Select	c.968-359T>A	intron	N/A	ENSP00000499655.2	Q6ZSZ5-4
ARHGEF18	ENST00000617428.4	TSL:1	c.-226-204T>A	intron	N/A	ENSP00000482647.4	Q6ZSZ5-2
ARHGEF18	ENST00000319670.14	TSL:1	c.-71-359T>A	intron	N/A	ENSP00000319200.8	A0A804CAZ4

Frequencies

GnomAD3 genomes

AF:

0.000908

AC:

138

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00149

AC:

231

AN:

154608

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000663

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000598

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.000978

AC:

1365

AN:

1395284

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

738

AN XY:

687806

show subpopulations

African (AFR)

AF:

0.0000956

AC:

AN:

31378

American (AMR)

AF:

0.000628

AC:

AN:

35016

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

365

AN:

25054

East Asian (EAS)

AF:

0.00

AC:

AN:

35632

South Asian (SAS)

AF:

0.000443

AC:

AN:

79058

European-Finnish (FIN)

AF:

0.0000611

AC:

AN:

49096

Middle Eastern (MID)

AF:

0.00620

AC:

AN:

5324

European-Non Finnish (NFE)

AF:

0.000721

AC:

776

AN:

1077010

Other (OTH)

AF:

0.00222

AC:

128

AN:

57716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000900

AC:

137

AN:

152156

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41544

American (AMR)

AF:

0.000327

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000912

AC:

AN:

67978

Other (OTH)

AF:

0.00332

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00244

Hom.:

Bravo

AF:

0.00106

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.096

PromoterAI

0.0084

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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