5-73752927-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001177693.2(ARHGEF28):c.200C>T(p.Thr67Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,613,836 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T67S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.363

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068123043).
• BP6: Variant 5-73752927-C-T is Benign according to our data. Variant chr5-73752927-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.200C>T	p.Thr67Met	missense_variant	4/36	ENST00000513042.7
ARHGEF28	NM_001080479.3	c.200C>T	p.Thr67Met	missense_variant	4/37
ARHGEF28	NM_001388078.1	c.200C>T	p.Thr67Met	missense_variant	4/35
ARHGEF28	NM_001388076.1	c.181+2943C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.200C>T	p.Thr67Met	missense_variant	4/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000706 AC: 175 AN: 247788 Hom.: 1 AF XY: 0.000900 AC XY: 121 AN XY: 134484

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00462

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461542 Hom.: 4 Cov.: 31 AF XY: 0.000519 AC XY: 377 AN XY: 727016

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00498

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74474

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00457

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000237 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000817 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ARHGEF28-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T;T;T;T;.;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0068	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.060	N;N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.20	T;T;T;T;T;T
Sift4G	Uncertain	0.040	D;D;D;D;D;D
Polyphen		0.42	B;.;B;.;.;B
Vest4		0.18
MVP		0.22
MPC		0.074
ClinPred		0.021	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs201258223; hg19: chr5-73048752;