19-7383172-C-T

Variant names:

• chr19-7383172-C-T
• rs72992636
• NM_001367823.1:c.936C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001367823.1(ARHGEF18):​c.936C>T​(p.Cys312Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00521 in 1,232,270 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (26 hom.)
• Consequence: ARHGEF18 NM_001367823.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.796
• Publications: 0 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-AS1 (HGNC:55284): (ARHGEF18 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 19-7383172-C-T is Benign according to our data. Variant chr19-7383172-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.796 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00303 (462/152286) while in subpopulation NFE AF = 0.00522 (355/68022). AF 95% confidence interval is 0.00477. There are 2 homozygotes in GnomAd4. There are 207 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	NM_001367823.1	MANE Select	c.936C>T	p.Cys312Cys	synonymous	Exon 10 of 29	NP_001354752.1	Q6ZSZ5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF18	ENST00000668164.2	MANE Select	c.936C>T	p.Cys312Cys	synonymous	Exon 10 of 29	ENSP00000499655.2	Q6ZSZ5-4
	ARHGEF18	ENST00000671891.2		c.1131C>T	p.Cys377Cys	synonymous	Exon 10 of 10	ENSP00000500339.2	A0A5F9ZHI8
	ARHGEF18-AS1	ENST00000795305.1		n.205+7404G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 152168 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00472 AC: 29 AN: 6148 AF XY: 0.00478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00909

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00551 AC: 5952 AN: 1079984 Hom.: 26 Cov.: 31 AF XY: 0.00535 AC XY: 2726 AN XY: 509878

African (AFR) AF: 0.000610 AC: 14 AN: 22966

American (AMR) AF: 0.00237 AC: 20 AN: 8422

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 21 AN: 14392

East Asian (EAS) AF: 0.00 AC: 0 AN: 26528

South Asian (SAS) AF: 0.00369 AC: 72 AN: 19492

European-Finnish (FIN) AF: 0.00265 AC: 57 AN: 21546

Middle Eastern (MID) AF: 0.00206 AC: 6 AN: 2914

European-Non Finnish (NFE) AF: 0.00609 AC: 5602 AN: 920046

Other (OTH) AF: 0.00366 AC: 160 AN: 43678

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152286 Hom.: 2 Cov.: 31 AF XY: 0.00278 AC XY: 207 AN XY: 74452

African (AFR) AF: 0.000794 AC: 33 AN: 41562

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68022

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00275 Hom.: 0

Bravo AF: 0.00301

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.0
DANN	Benign	0.68
PhyloP100		0.80

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: rs72992636; hg19: chr19-7448058;