rs6453022

Positions:

• chr5-73780686-C-A
• chr5-73780686-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.851C>A​(p.Pro284Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,553,786 control chromosomes in the GnomAD database, including 206,069 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 0.56 (23978 hom., cov: 30)
  • Exomes 𝑓: 0.51 (182091 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.90

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]

ENSG00000249293 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4842926E-6).
• BP6: Variant 5-73780686-C-A is Benign according to our data. Variant chr5-73780686-C-A is described in ClinVar as [Benign]. Clinvar id is 257378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73780686-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.851C>A	p.Pro284Gln	missense_variant	7/36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.851C>A	p.Pro284Gln	missense_variant	7/37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.851C>A	p.Pro284Gln	missense_variant	7/35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.557C>A	p.Pro186Gln	missense_variant	6/35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.851C>A	p.Pro284Gln	missense_variant	7/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84189 AN: 151482 Hom.: 23930 Cov.: 30

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.525 AC: 86213 AN: 164138 Hom.: 22970 AF XY: 0.521 AC XY: 45127 AN XY: 86672

Gnomad AFR exome AF: 0.685

Gnomad AMR exome AF: 0.588

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.505

Gnomad SAS exome AF: 0.531

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.508 AC: 712262 AN: 1402184 Hom.: 182091 Cov.: 41 AF XY: 0.507 AC XY: 351054 AN XY: 692062

Gnomad4 AFR exome AF: 0.696

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.533

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.521

GnomAD4 genome AF: 0.556 AC: 84289 AN: 151602 Hom.: 23978 Cov.: 30 AF XY: 0.556 AC XY: 41153 AN XY: 74026

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.496

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.486

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.542

Alfa AF: 0.505 Hom.: 44349

Bravo AF: 0.569

TwinsUK AF: 0.510 AC: 1890

ALSPAC AF: 0.506 AC: 1949

ESP6500AA AF: 0.703 AC: 2702

ESP6500EA AF: 0.507 AC: 4177

ExAC AF: 0.414 AC: 43300

Asia WGS AF: 0.544 AC: 1893 AN: 3478

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.0028	.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T;T;T;.;.
MetaRNN	Benign	0.0000015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.030	N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.89	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0	B;.;B;.;B
Vest4		0.048
MPC		0.065
ClinPred		0.0020	T
GERP RS		-0.022
Varity_R		0.052
gMVP		0.16

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: rs6453022; hg19: chr5-73076511; COSMIC: COSV55249108;