rs146562116

Variant names:

• chr5-73894487-C-T
• rs146562116
• NM_001177693.2:c.3753C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):​c.3753C>T​(p.Asp1251Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,613,868 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (114 hom., cov: 33)
  • Exomes 𝑓: 0.020 (1104 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.231
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-73894487-C-T is Benign according to our data. Variant chr5-73894487-C-T is described in ClinVar as Benign. ClinVar VariationId is 257369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0925 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.3753C>T	p.Asp1251Asp	synonymous	Exon 29 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.3753C>T	p.Asp1251Asp	synonymous	Exon 29 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.3753C>T	p.Asp1251Asp	synonymous	Exon 29 of 35	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.3753C>T	p.Asp1251Asp	synonymous	Exon 29 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.3753C>T	p.Asp1251Asp	synonymous	Exon 28 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.3753C>T	p.Asp1251Asp	synonymous	Exon 28 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3018 AN: 152148 Hom.: 112 Cov.: 33

Gnomad AFR AF: 0.00657

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0961

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0384 AC: 9554 AN: 248892 AF XY: 0.0326

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0202 AC: 29485 AN: 1461602 Hom.: 1104 Cov.: 31 AF XY: 0.0195 AC XY: 14147 AN XY: 727074

African (AFR) AF: 0.00454 AC: 152 AN: 33476

American (AMR) AF: 0.179 AC: 7983 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 507 AN: 26132

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39700

South Asian (SAS) AF: 0.0282 AC: 2430 AN: 86236

European-Finnish (FIN) AF: 0.00581 AC: 310 AN: 53398

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5768

European-Non Finnish (NFE) AF: 0.0151 AC: 16768 AN: 1111842

Other (OTH) AF: 0.0200 AC: 1208 AN: 60374

GnomAD4 genome AF: 0.0199 AC: 3029 AN: 152266 Hom.: 114 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74454

African (AFR) AF: 0.00657 AC: 273 AN: 41550

American (AMR) AF: 0.0966 AC: 1478 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5180

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4820

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 974 AN: 68022

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0155 Hom.: 18

Bravo AF: 0.0283

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.9
DANN	Benign	0.36
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs146562116; hg19: chr5-73190312; COSMIC: COSV104382974;