chr19-7444215-A-G

Variant names:

• chr19-7444215-A-G
• rs987233144
• NM_001367823.1:c.1372A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_001367823.1(ARHGEF18):​c.1372A>G​(p.Thr458Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ARHGEF18 NM_001367823.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 19-7444215-A-G is Pathogenic according to our data. Variant chr19-7444215-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 417754.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	NM_001367823.1	MANE Select	c.1372A>G	p.Thr458Ala	missense	Exon 14 of 29	NP_001354752.1	Q6ZSZ5-4
	ARHGEF18	NM_001130955.2		c.646A>G	p.Thr216Ala	missense	Exon 4 of 20	NP_001124427.2	A0A3B3IPE9
	ARHGEF18	NM_001367824.1		c.334A>G	p.Thr112Ala	missense	Exon 5 of 20	NP_001354753.1	Q6ZSZ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	ENST00000668164.2	MANE Select	c.1372A>G	p.Thr458Ala	missense	Exon 14 of 29	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000617428.4	TSL:1	c.334A>G	p.Thr112Ala	missense	Exon 5 of 20	ENSP00000482647.4	Q6ZSZ5-2
	ARHGEF18	ENST00000319670.14	TSL:1	c.334A>G	p.Thr112Ala	missense	Exon 5 of 20	ENSP00000319200.8	A0A804CAZ4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460904 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726704

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Retinitis pigmentosa 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.63	D
PhyloP100		9.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		0.87		Loss of catalytic residue at T270 (P = 0.0331)
MVP		0.39
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.71
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs987233144; hg19: chr19-7509101;