rs2973571

Positions:

• chr5-73846471-C-T

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.1631C>T​(p.Ser544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,611,306 control chromosomes in the GnomAD database, including 60,119 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 0.24 (4596 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55523 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0500

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]

ARHGEF28 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004041642).
• BP6: Variant 5-73846471-C-T is Benign according to our data. Variant chr5-73846471-C-T is described in ClinVar as [Benign]. Clinvar id is 257358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73846471-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.1631C>T	p.Ser544Leu	missense_variant	12/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1631C>T	p.Ser544Leu	missense_variant	12/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35844 AN: 151854 Hom.: 4595 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.230

GnomAD3 exomes AF: 0.245 AC: 61011 AN: 248670 Hom.: 8015 AF XY: 0.243 AC XY: 32721 AN XY: 134892

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.0638

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.271 AC: 395870 AN: 1459334 Hom.: 55523 Cov.: 33 AF XY: 0.269 AC XY: 194991 AN XY: 726074

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.0584

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.259

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.236 AC: 35855 AN: 151972 Hom.: 4596 Cov.: 31 AF XY: 0.232 AC XY: 17197 AN XY: 74272

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.0714

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.227

Alfa AF: 0.266 Hom.: 11821

Bravo AF: 0.236

TwinsUK AF: 0.295 AC: 1095

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.160 AC: 586

ESP6500EA AF: 0.273 AC: 2232

ExAC AF: 0.240 AC: 28977

Asia WGS AF: 0.120 AC: 419 AN: 3478

EpiCase AF: 0.272

EpiControl AF: 0.272

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, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	0.063
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0060	.;.;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.71	T;T;T;.;.;T
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.12	N;N;N;N;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.78	N;N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.17	T;T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B;.
Vest4		0.040
MPC		0.063
ClinPred		0.0072	T
GERP RS		-0.95
Varity_R		0.026
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2973571; hg19: chr5-73142296; COSMIC: COSV55251712;