5-73863776-T-C

Variant names:

• chr5-73863776-T-C
• rs6869486
• NM_001177693.2:c.2048-1041T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080479.3(ARHGEF28):​c.2048-1041T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 151,466 control chromosomes in the GnomAD database, including 8,787 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8787 hom., cov: 30)
• Consequence: ARHGEF28 NM_001080479.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.145
• Publications: 3 publications found

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]

ARHGEF28 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080479.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.2048-1041T>C		intron	N/A	NP_001171164.1
	ARHGEF28	NM_001080479.3		c.2048-1041T>C		intron	N/A	NP_001073948.2
	ARHGEF28	NM_001388078.1		c.2048-1041T>C		intron	N/A	NP_001375007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.2048-1041T>C		intron	N/A	ENSP00000441436.1
	ARHGEF28	ENST00000437974.5	TSL:1	c.2048-1041T>C		intron	N/A	ENSP00000411459.1
	ARHGEF28	ENST00000426542.6	TSL:1	c.2048-1041T>C		intron	N/A	ENSP00000412175.2

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46242 AN: 151348 Hom.: 8781 Cov.: 30

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.304

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.306 AC: 46300 AN: 151466 Hom.: 8787 Cov.: 30 AF XY: 0.306 AC XY: 22655 AN XY: 73996

African (AFR) AF: 0.533 AC: 21963 AN: 41188

American (AMR) AF: 0.208 AC: 3158 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3468

East Asian (EAS) AF: 0.377 AC: 1941 AN: 5142

South Asian (SAS) AF: 0.336 AC: 1608 AN: 4790

European-Finnish (FIN) AF: 0.186 AC: 1954 AN: 10512

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14042 AN: 67880

Other (OTH) AF: 0.307 AC: 645 AN: 2104

Alfa AF: 0.244 Hom.: 15983

Bravo AF: 0.319

Asia WGS AF: 0.361 AC: 1256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6869486; hg19: chr5-73159601;