NM_001177693.2:c.33+128G>A

Variant names:

• chr5-73685012-G-A
• rs16870681
• NM_001177693.2:c.33+128G>A

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.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
• Publications: 7 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 -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 VariationId 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.

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.33+128G>A		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.33+128G>A		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.33+128G>A		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.33+128G>A		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.33+128G>A		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.33+128G>A		intron	N/A	ENSP00000412175.2	Q8N1W1-1

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

African (AFR) AF: 0.191 AC: 3334 AN: 17498

American (AMR) AF: 0.144 AC: 2621 AN: 18206

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 4682 AN: 16412

East Asian (EAS) AF: 0.0285 AC: 863 AN: 30242

South Asian (SAS) AF: 0.142 AC: 6211 AN: 43804

European-Finnish (FIN) AF: 0.230 AC: 9829 AN: 42698

Middle Eastern (MID) AF: 0.184 AC: 752 AN: 4078

European-Non Finnish (NFE) AF: 0.241 AC: 125500 AN: 521364

Other (OTH) AF: 0.220 AC: 7532 AN: 34262

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

African (AFR) AF: 0.191 AC: 7943 AN: 41486

American (AMR) AF: 0.165 AC: 2518 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3472

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5170

South Asian (SAS) AF: 0.157 AC: 754 AN: 4814

European-Finnish (FIN) AF: 0.222 AC: 2349 AN: 10562

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16426 AN: 68004

Other (OTH) AF: 0.195 AC: 412 AN: 2108

Alfa AF: 0.229 Hom.: 15854

Bravo AF: 0.204

Asia WGS AF: 0.107 AC: 375 AN: 3478

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	0.043
DANN	Benign	0.82
PhyloP100		-1.9
PromoterAI		0.0036	Neutral
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: rs16870681; hg19: chr5-72980837;