5-73685012-G-A

Position:

• chr5-73685012-G-A

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.33+128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 880,652 control chromosomes in the GnomAD database, including 22,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3511 hom., cov: 32)
  • Exomes 𝑓: 0.22 (19025 hom.)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94

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 (BayesDel_noAF=-0.91).
• BP6: Variant 5-73685012-G-A is Benign according to our data. Variant chr5-73685012-G-A is described in ClinVar as [Benign]. Clinvar id is 1232228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.33+128G>A		intron_variant		ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.33+128G>A		intron_variant			NP_001073948.2
ARHGEF28	NM_001388076.1	c.33+128G>A		intron_variant			NP_001375005.1
ARHGEF28	NM_001388078.1	c.33+128G>A		intron_variant			NP_001375007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.33+128G>A		intron_variant		5	NM_001177693.2	ENSP00000441436

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31782 AN: 151970 Hom.: 3505 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.221 AC: 161324 AN: 728564 Hom.: 19025 AF XY: 0.219 AC XY: 80841 AN XY: 368326

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.0285

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.209 AC: 31824 AN: 152088 Hom.: 3511 Cov.: 32 AF XY: 0.205 AC XY: 15223 AN XY: 74348

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.0358

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.195

Alfa AF: 0.232 Hom.: 7322

Bravo AF: 0.204

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.043
DANN	Benign	0.82

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: rs16870681; hg19: chr5-72980837;