rs2973568

chr5-73849020-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):c.1680A>G(p.Ser560=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,575,968 control chromosomes in the GnomAD database, including 282,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35574 hom., cov: 32)
  • Exomes 𝑓: 0.59 (247057 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.175

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-73849020-A-G is Benign according to our data. Variant chr5-73849020-A-G is described in ClinVar as [Benign]. Clinvar id is 257359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73849020-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.175 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.1680A>G	p.Ser560=	synonymous_variant	13/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1680A>G	p.Ser560=	synonymous_variant	13/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101220 AN: 151854 Hom.: 35507 Cov.: 32

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.655

GnomAD3 exomes AF: 0.596 AC: 119906 AN: 201102 Hom.: 36586 AF XY: 0.591 AC XY: 63305 AN XY: 107168

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.639

Gnomad ASJ exome AF: 0.584

Gnomad EAS exome AF: 0.523

Gnomad SAS exome AF: 0.613

Gnomad FIN exome AF: 0.524

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.585 AC: 833504 AN: 1423994 Hom.: 247057 Cov.: 41 AF XY: 0.584 AC XY: 411654 AN XY: 704906

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.637

Gnomad4 ASJ exome AF: 0.576

Gnomad4 EAS exome AF: 0.478

Gnomad4 SAS exome AF: 0.613

Gnomad4 FIN exome AF: 0.533

Gnomad4 NFE exome AF: 0.577

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.667 AC: 101348 AN: 151974 Hom.: 35574 Cov.: 32 AF XY: 0.662 AC XY: 49124 AN XY: 74250

Gnomad4 AFR AF: 0.899

Gnomad4 AMR AF: 0.643

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.657

Alfa AF: 0.593 Hom.: 32921

Bravo AF: 0.689

Asia WGS AF: 0.622 AC: 2159 AN: 3476

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic 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	-	- -

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	-0.47
Cadd	Benign	7.1
Dann	Benign	0.64

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: rs2973568; hg19: chr5-73144845; COSMIC: COSV55249148;