5-73853291-T-C

Variant names:

• chr5-73853291-T-C
• rs17553316
• NM_001177693.2:c.1790+599T>C

Variant summary

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

The NM_001177693.2(ARHGEF28):​c.1790+599T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 152,292 control chromosomes in the GnomAD database, including 449 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 0.073 (449 hom., cov: 33)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.987
• Publications: 5 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, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177693.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.1790+599T>C		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.1790+599T>C		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.1790+599T>C		intron	N/A	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.1790+599T>C		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.1790+599T>C		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.1790+599T>C		intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11135 AN: 152174 Hom.: 449 Cov.: 33

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0736

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

GnomAD4 genome AF: 0.0732 AC: 11148 AN: 152292 Hom.: 449 Cov.: 33 AF XY: 0.0725 AC XY: 5395 AN XY: 74464

African (AFR) AF: 0.0755 AC: 3139 AN: 41552

American (AMR) AF: 0.0475 AC: 727 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3470

East Asian (EAS) AF: 0.0245 AC: 127 AN: 5182

South Asian (SAS) AF: 0.0791 AC: 382 AN: 4828

European-Finnish (FIN) AF: 0.0823 AC: 873 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5467 AN: 68030

Other (OTH) AF: 0.0728 AC: 154 AN: 2114

Alfa AF: 0.0764 Hom.: 823

Bravo AF: 0.0702

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.70
PhyloP100		0.99
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: rs17553316; hg19: chr5-73149116;