rs423333

Positions:

• chr5-73923129-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000437974.5(ARHGEF28):​c.4991C>T​(p.Pro1664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,534,866 control chromosomes in the GnomAD database, including 36,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7666 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28844 hom.)
• Consequence: ARHGEF28 ENST00000437974.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.00

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=4.4029228E-5).
• BP6: Variant 5-73923129-C-T is Benign according to our data. Variant chr5-73923129-C-T is described in ClinVar as [Benign]. Clinvar id is 257375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73923129-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.4948+11554C>T		intron_variant		ENST00000513042.7
ARHGEF28	NM_001080479.3	c.4991C>T	p.Pro1664Leu	missense_variant	36/37
ARHGEF28	NM_001244364.2	c.4009+11554C>T		intron_variant
ARHGEF28	NM_001388076.1	c.4654+11554C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4948+11554C>T		intron_variant		5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42216 AN: 151816 Hom.: 7641 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.246 AC: 33596 AN: 136596 Hom.: 5281 AF XY: 0.239 AC XY: 17770 AN XY: 74290

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.308

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.190 AC: 263266 AN: 1382932 Hom.: 28844 Cov.: 32 AF XY: 0.193 AC XY: 131438 AN XY: 682408

Gnomad4 AFR exome AF: 0.512

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.278 AC: 42306 AN: 151934 Hom.: 7666 Cov.: 32 AF XY: 0.276 AC XY: 20498 AN XY: 74264

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.232

Alfa AF: 0.181 Hom.: 6836

Bravo AF: 0.299

TwinsUK AF: 0.166 AC: 614

ALSPAC AF: 0.165 AC: 634

ExAC AF: 0.232 AC: 4005

Asia WGS AF: 0.259 AC: 900 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, Academic 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 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
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.37
DANN	Benign	0.42
DEOGEN2	Benign	0.0067	.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.48	T;.;T
MetaRNN	Benign	0.000044	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.0070
Sift	Benign	1.0	T;T;T
Sift4G	Uncertain	0.053	T;T;D
Polyphen		0.0	.;.;B
Vest4		0.058
MPC		0.071
ClinPred		0.00072	T
GERP RS		-6.6
gMVP		0.072

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs423333; hg19: chr5-73218954; COSMIC: COSV55249161;