rs3749645

chr5-73883847-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.3018C>T(p.Tyr1006=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,569,962 control chromosomes in the GnomAD database, including 13,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1560 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12267 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.25

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=-0.34).
• BP6: Variant 5-73883847-C-T is Benign according to our data. Variant chr5-73883847-C-T is described in ClinVar as [Benign]. Clinvar id is 257366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73883847-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.3018C>T	p.Tyr1006=	synonymous_variant	24/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.3018C>T	p.Tyr1006=	synonymous_variant	24/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20591 AN: 151828 Hom.: 1560 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.0896

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.128 AC: 24278 AN: 189534 Hom.: 1811 AF XY: 0.130 AC XY: 13131 AN XY: 100804

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.276

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.126 AC: 178372 AN: 1418016 Hom.: 12267 Cov.: 30 AF XY: 0.126 AC XY: 88612 AN XY: 701144

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0793

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.136 AC: 20602 AN: 151946 Hom.: 1560 Cov.: 32 AF XY: 0.136 AC XY: 10080 AN XY: 74250

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0893

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.136

Alfa AF: 0.121 Hom.: 2312

Bravo AF: 0.137

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:1

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	-0.34
Cadd	Benign	7.9
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3749645; hg19: chr5-73179672; COSMIC: COSV55257068; COSMIC: COSV55257068;