rs17634865

chr5-73909892-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.4642C>T(p.Pro1548Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,506,738 control chromosomes in the GnomAD database, including 1,179 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 0.037 (107 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1072 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.07

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=0.0023434758).
• BP6: Variant 5-73909892-C-T is Benign according to our data. Variant chr5-73909892-C-T is described in ClinVar as [Benign]. Clinvar id is 257373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73909892-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.4642C>T	p.Pro1548Ser	missense_variant	34/36	ENST00000513042.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4642C>T	p.Pro1548Ser	missense_variant	34/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5644 AN: 152058 Hom.: 107 Cov.: 31

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0333 AC: 4715 AN: 141702 Hom.: 104 AF XY: 0.0352 AC XY: 2737 AN XY: 77724

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.00980

Gnomad EAS exome AF: 0.000137

Gnomad SAS exome AF: 0.0624

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0374 AC: 50613 AN: 1354562 Hom.: 1072 Cov.: 30 AF XY: 0.0381 AC XY: 25356 AN XY: 665428

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.0244

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0591

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0352

GnomAD4 genome AF: 0.0371 AC: 5646 AN: 152176 Hom.: 107 Cov.: 31 AF XY: 0.0396 AC XY: 2948 AN XY: 74412

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0604

Gnomad4 FIN AF: 0.0625

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0368 Hom.: 170

Bravo AF: 0.0343

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.0276 AC: 89

ESP6500EA AF: 0.0265 AC: 195

ExAC AF: 0.0325 AC: 3738

Asia WGS AF: 0.0300 AC: 105 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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.0050
Dann	Benign	0.47
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.26	T;T;T;.;.;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.24	N;N;N;N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.84	T;T;T;T;T;T;T
Sift4G	Benign	0.72	T;T;T;T;T;T;T
Polyphen		0.0030	B;.;B;.;B;.;B
Vest4		0.067
MPC		0.071
ClinPred		0.000019	T
GERP RS		-4.5
Varity_R		0.014
gMVP		0.094

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: rs17634865; hg19: chr5-73205717; COSMIC: COSV104383009; COSMIC: COSV104383009;