5-73749936-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001177693.2(ARHGEF28):c.133A>G(p.Met45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.361

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010992199).
• BP6: Variant 5-73749936-A-G is Benign according to our data. Variant chr5-73749936-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2511392.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.133A>G	p.Met45Val	missense_variant	3/36	ENST00000513042.7
ARHGEF28	NM_001080479.3	c.133A>G	p.Met45Val	missense_variant	3/37
ARHGEF28	NM_001388078.1	c.133A>G	p.Met45Val	missense_variant	3/35
ARHGEF28	NM_001388076.1	c.133A>G	p.Met45Val	missense_variant	3/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.133A>G	p.Met45Val	missense_variant	3/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000257 AC: 64 AN: 249238 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 135202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000223

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000330 AC: 40

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ARHGEF28-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.60
Dann	Benign	0.36
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.62	T;T;T;T;.;.
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N;N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.15	N;N;N;N;N;N
REVEL	Benign	0.028
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;B
Vest4		0.21
MVP		0.055
MPC		0.071
ClinPred		0.012	T
GERP RS		-1.1
Varity_R		0.020
gMVP		0.21

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: rs200289106; hg19: chr5-73045761;