rs2973558

Positions:

• chr5-73868140-C-A

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.2338C>A​(p.His780Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,607,836 control chromosomes in the GnomAD database, including 80,555 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 0.29 (6596 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73959 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.160

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=2.4458766E-4).
• BP6: Variant 5-73868140-C-A is Benign according to our data. Variant chr5-73868140-C-A is described in ClinVar as [Benign]. Clinvar id is 257364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73868140-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.2338C>A	p.His780Asn	missense_variant	20/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.2338C>A	p.His780Asn	missense_variant	20/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43360 AN: 151954 Hom.: 6587 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.284

GnomAD3 exomes AF: 0.299 AC: 71577 AN: 239616 Hom.: 11522 AF XY: 0.290 AC XY: 37536 AN XY: 129600

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.314 AC: 457341 AN: 1455762 Hom.: 73959 Cov.: 38 AF XY: 0.310 AC XY: 223952 AN XY: 723452

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.285 AC: 43398 AN: 152074 Hom.: 6596 Cov.: 32 AF XY: 0.280 AC XY: 20850 AN XY: 74342

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.281

Alfa AF: 0.307 Hom.: 13872

Bravo AF: 0.292

TwinsUK AF: 0.338 AC: 1254

ALSPAC AF: 0.336 AC: 1295

ESP6500AA AF: 0.202 AC: 792

ESP6500EA AF: 0.311 AC: 2584

ExAC AF: 0.285 AC: 34448

Asia WGS AF: 0.156 AC: 544 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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, 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	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.0
DANN	Benign	0.79
DEOGEN2	Benign	0.0036	.;.;T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.046	T;T;T;.;.;T
MetaRNN	Benign	0.00024	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N;N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.0020	B;.;B;.;B;.
Vest4		0.033
MPC		0.076
ClinPred		0.0057	T
GERP RS		-0.56
Varity_R		0.046
gMVP		0.20

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: rs2973558; hg19: chr5-73163965; COSMIC: COSV55257053; COSMIC: COSV55257053;