5-73752994-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001177693.2(ARHGEF28):c.267G>A(p.Val89=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,496 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (164 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.16

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-73752994-G-A is Benign according to our data. Variant chr5-73752994-G-A is described in ClinVar as [Benign]. Clinvar id is 257365.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-73752994-G-A is described in Lovd as [Benign]. Variant chr5-73752994-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00877 (1336/152334) while in subpopulation SAS AF= 0.0195 (94/4822). AF 95% confidence interval is 0.0163. There are 13 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.267G>A	p.Val89=	synonymous_variant	4/36	ENST00000513042.7
ARHGEF28	NM_001080479.3	c.267G>A	p.Val89=	synonymous_variant	4/37
ARHGEF28	NM_001388078.1	c.267G>A	p.Val89=	synonymous_variant	4/35
ARHGEF28	NM_001388076.1	c.181+3010G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.267G>A	p.Val89=	synonymous_variant	4/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.00876 AC: 1334 AN: 152216 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0108 AC: 2665 AN: 247902 Hom.: 33 AF XY: 0.0118 AC XY: 1583 AN XY: 134464

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.0334

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0216

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0118 AC: 17245 AN: 1461162 Hom.: 164 Cov.: 31 AF XY: 0.0123 AC XY: 8953 AN XY: 726782

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00466

Gnomad4 ASJ exome AF: 0.0352

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.00877 AC: 1336 AN: 152334 Hom.: 13 Cov.: 32 AF XY: 0.00863 AC XY: 643 AN XY: 74486

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0131 Hom.: 15

Bravo AF: 0.00900

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17552682; hg19: chr5-73048819;