rs17634853

chr5-73909638-G-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.4388G>A(p.Arg1463Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0377 in 1,548,766 control chromosomes in the GnomAD database, including 1,234 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1463W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (115 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1119 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.94

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=0.001647383).
• BP6: Variant 5-73909638-G-A is Benign according to our data. Variant chr5-73909638-G-A is described in ClinVar as [Benign]. Clinvar id is 257371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73909638-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.4388G>A	p.Arg1463Gln	missense_variant	34/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4388G>A	p.Arg1463Gln	missense_variant	34/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5482 AN: 152174 Hom.: 114 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0374 AC: 5374 AN: 143664 Hom.: 126 AF XY: 0.0386 AC XY: 2988 AN XY: 77458

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0000937

Gnomad SAS exome AF: 0.0571

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0379 AC: 52881 AN: 1396474 Hom.: 1119 Cov.: 31 AF XY: 0.0386 AC XY: 26550 AN XY: 688544

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.0566

Gnomad4 FIN exome AF: 0.0604

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.0361 AC: 5494 AN: 152292 Hom.: 115 Cov.: 32 AF XY: 0.0384 AC XY: 2863 AN XY: 74466

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.0249

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.0629

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0343 Hom.: 28

Bravo AF: 0.0330

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0311 AC: 120

ESP6500AA AF: 0.0266 AC: 103

ESP6500EA AF: 0.0251 AC: 199

ExAC AF: 0.0207 AC: 2000

Asia WGS AF: 0.0290 AC: 102 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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.073
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T;.;.;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.;.
MutationTaster	Benign	0.94	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.43	N;N;N;N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.35	T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T
Polyphen		0.33	B;.;B;.;B;.;B
Vest4		0.12
MPC		0.094
ClinPred		0.0076	T
GERP RS		5.2
Varity_R		0.092
gMVP		0.060

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: rs17634853; hg19: chr5-73205463; COSMIC: COSV55248394; COSMIC: COSV55248394;