rs7714670

chr5-73776529-T-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.673T>C(p.Trp225Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,608,154 control chromosomes in the GnomAD database, including 162,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.42 (13489 hom., cov: 31)
  • Exomes 𝑓: 0.45 (148681 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.243

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=1.5380979E-4).
• BP6: Variant 5-73776529-T-C is Benign according to our data. Variant chr5-73776529-T-C is described in ClinVar as [Benign]. Clinvar id is 257376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73776529-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.673T>C	p.Trp225Arg	missense_variant	6/36	ENST00000513042.7
ARHGEF28	NM_001080479.3	c.673T>C	p.Trp225Arg	missense_variant	6/37
ARHGEF28	NM_001388078.1	c.673T>C	p.Trp225Arg	missense_variant	6/35
ARHGEF28	NM_001388076.1	c.379T>C	p.Trp127Arg	missense_variant	5/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.673T>C	p.Trp225Arg	missense_variant	6/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63519 AN: 151794 Hom.: 13485 Cov.: 31

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.411

GnomAD3 exomes AF: 0.427 AC: 105730 AN: 247566 Hom.: 22933 AF XY: 0.426 AC XY: 57250 AN XY: 134344

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.330

Gnomad SAS exome AF: 0.384

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.450 AC: 655056 AN: 1456240 Hom.: 148681 Cov.: 38 AF XY: 0.448 AC XY: 324548 AN XY: 724436

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.466

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.418 AC: 63553 AN: 151914 Hom.: 13489 Cov.: 31 AF XY: 0.418 AC XY: 31028 AN XY: 74226

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.414

Alfa AF: 0.442 Hom.: 36694

Bravo AF: 0.413

TwinsUK AF: 0.473 AC: 1754

ALSPAC AF: 0.476 AC: 1835

ESP6500AA AF: 0.359 AC: 1467

ESP6500EA AF: 0.452 AC: 3811

ExAC AF: 0.427 AC: 51645

Asia WGS AF: 0.337 AC: 1175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, 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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	12
Dann	Benign	0.46
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.45	T;T;T;.;.
MetaRNN	Benign	0.00015	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.51	N;N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.88	T;T;T;T;T
Sift4G	Benign	0.91	T;T;T;T;T
Polyphen		0.0	B;.;B;.;B
Vest4		0.035
MutPred		0.32		Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);
MPC		0.12
ClinPred		0.00098	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.26

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: rs7714670; hg19: chr5-73072354; COSMIC: COSV55249093; COSMIC: COSV55249093;