rs17552626

Variant names:

• chr5-73749681-T-C
• rs17552626
• NM_001177693.2:c.34-156T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001177693.2(ARHGEF28):​c.34-156T>C 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 152,062 control chromosomes in the GnomAD database, including 4,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.22 (4003 hom., cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.197
• 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: AR, AD, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-73749681-T-C is Benign according to our data. Variant chr5-73749681-T-C is described in ClinVar as Benign. ClinVar VariationId is 1278356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 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.34-156T>C		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.34-156T>C		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.34-156T>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.34-156T>C		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.34-156T>C		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.34-156T>C		intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33265 AN: 151944 Hom.: 4000 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.232

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

GnomAD4 genome AF: 0.219 AC: 33271 AN: 152062 Hom.: 4003 Cov.: 32 AF XY: 0.219 AC XY: 16291 AN XY: 74332

African (AFR) AF: 0.128 AC: 5321 AN: 41500

American (AMR) AF: 0.190 AC: 2910 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3472

East Asian (EAS) AF: 0.132 AC: 682 AN: 5170

South Asian (SAS) AF: 0.198 AC: 951 AN: 4812

European-Finnish (FIN) AF: 0.304 AC: 3205 AN: 10558

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18384 AN: 67952

Other (OTH) AF: 0.230 AC: 485 AN: 2112

Alfa AF: 0.248 Hom.: 6245

Bravo AF: 0.206

Asia WGS AF: 0.158 AC: 551 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.76
PhyloP100		-0.20
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: rs17552626; hg19: chr5-73045506; COSMIC: COSV55257506;