rs146562116

chr5-73894487-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):c.3753C>T(p.Asp1251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,613,868 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (114 hom., cov: 33)
  • Exomes 𝑓: 0.020 (1104 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.231

Genes affected

ARHGEF28 (HGNC:30322): (Rho guanine nucleotide exchange factor 28) This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-73894487-C-T is Benign according to our data. Variant chr5-73894487-C-T is described in ClinVar as [Benign]. Clinvar id is 257369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73894487-C-T is described in Lovd as [Likely_benign]. Variant chr5-73894487-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.3753C>T	p.Asp1251=	synonymous_variant	29/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.3753C>T	p.Asp1251=	synonymous_variant	29/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3018 AN: 152148 Hom.: 112 Cov.: 33

Gnomad AFR AF: 0.00657

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0961

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0384 AC: 9554 AN: 248892 Hom.: 776 AF XY: 0.0326 AC XY: 4406 AN XY: 135040

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0202 AC: 29485 AN: 1461602 Hom.: 1104 Cov.: 31 AF XY: 0.0195 AC XY: 14147 AN XY: 727074

Gnomad4 AFR exome AF: 0.00454

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.0282

Gnomad4 FIN exome AF: 0.00581

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0199 AC: 3029 AN: 152266 Hom.: 114 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74454

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.0966

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0155 Hom.: 18

Bravo AF: 0.0283

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	6.9
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs146562116; hg19: chr5-73190312; COSMIC: COSV104382974; COSMIC: COSV104382974;