rs2973566

Positions:

• chr5-73852656-G-A
• chr5-73852656-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001177693.2(ARHGEF28):​c.1754G>A​(p.Arg585Lys) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,611,420 control chromosomes in the GnomAD database, including 61,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4488 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57358 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.54

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014189482).
• BP6: Variant 5-73852656-G-A is Benign according to our data. Variant chr5-73852656-G-A is described in ClinVar as [Benign]. Clinvar id is 257360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73852656-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.1754G>A	p.Arg585Lys	missense_variant	14/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1754G>A	p.Arg585Lys	missense_variant	14/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34874 AN: 151912 Hom.: 4488 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.246 AC: 61060 AN: 248712 Hom.: 8139 AF XY: 0.243 AC XY: 32824 AN XY: 134952

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0635

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.275 AC: 400918 AN: 1459388 Hom.: 57358 Cov.: 33 AF XY: 0.272 AC XY: 197413 AN XY: 726066

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.0581

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.229 AC: 34884 AN: 152032 Hom.: 4488 Cov.: 32 AF XY: 0.225 AC XY: 16745 AN XY: 74346

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.0705

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.223

Alfa AF: 0.263 Hom.: 13082

Bravo AF: 0.229

TwinsUK AF: 0.304 AC: 1126

ALSPAC AF: 0.299 AC: 1152

ESP6500AA AF: 0.127 AC: 477

ESP6500EA AF: 0.278 AC: 2289

ExAC AF: 0.241 AC: 29071

Asia WGS AF: 0.120 AC: 417 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.276

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T;T;.;.;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.016	D;D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D;D;T
Polyphen		0.99	D;.;D;.;D;.
Vest4		0.34
MPC		0.39
ClinPred		0.022	T
GERP RS		6.2
Varity_R		0.18
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2973566; hg19: chr5-73148481; COSMIC: COSV55255528; COSMIC: COSV55255528;