rs188040167

Positions:

• chr5-73901264-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001177693.2(ARHGEF28):​c.4054G>A​(p.Val1352Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,612,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (12 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.26

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044407547).
• BP6: Variant 5-73901264-G-A is Benign according to our data. Variant chr5-73901264-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73901264-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.4054G>A	p.Val1352Ile	missense_variant	31/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4054G>A	p.Val1352Ile	missense_variant	31/36	5	NM_001177693.2	ENSP00000441436

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00293 AC: 728 AN: 248556 Hom.: 1 AF XY: 0.00298 AC XY: 402 AN XY: 134762

Gnomad AFR exome AF: 0.000843

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00139

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00400 AC: 5848 AN: 1460778 Hom.: 12 Cov.: 30 AF XY: 0.00399 AC XY: 2900 AN XY: 726628

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00556

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.00314 AC: 478 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74402

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00393 Hom.: 2

Bravo AF: 0.00284

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00126 AC: 5

ESP6500EA AF: 0.00494 AC: 41

ExAC AF: 0.00304 AC: 367

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00380

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ARHGEF28: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0091	.;.;T;.;T;.;T
Eigen	Benign	0.044
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	T;T;T;.;.;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0044	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N;N;N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.19	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.23	B;.;P;.;P;.;P
Vest4		0.11
MVP		0.20
MPC		0.063
ClinPred		0.0068	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.058

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: rs188040167; hg19: chr5-73197089; COSMIC: COSV55262059;