rs17552682

Variant names:

• chr5-73752994-G-A
• rs17552682
• NM_001177693.2:c.267G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001177693.2(ARHGEF28):​c.267G>A​(p.Val89Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,496 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (164 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.16
• Publications: 4 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=-0.42).
• BP6: Variant 5-73752994-G-A is Benign according to our data. Variant chr5-73752994-G-A is described in ClinVar as Benign. ClinVar VariationId is 257365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00877 (1336/152334) while in subpopulation SAS AF = 0.0195 (94/4822). AF 95% confidence interval is 0.0163. There are 13 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

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.267G>A	p.Val89Val	synonymous	Exon 4 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.267G>A	p.Val89Val	synonymous	Exon 4 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.267G>A	p.Val89Val	synonymous	Exon 4 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.267G>A	p.Val89Val	synonymous	Exon 4 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.267G>A	p.Val89Val	synonymous	Exon 3 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.267G>A	p.Val89Val	synonymous	Exon 3 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.00876 AC: 1334 AN: 152216 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0108 AC: 2665 AN: 247902 AF XY: 0.0118

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.0334

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0118 AC: 17245 AN: 1461162 Hom.: 164 Cov.: 31 AF XY: 0.0123 AC XY: 8953 AN XY: 726782

African (AFR) AF: 0.00146 AC: 49 AN: 33474

American (AMR) AF: 0.00466 AC: 208 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 921 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.0199 AC: 1709 AN: 86048

European-Finnish (FIN) AF: 0.00176 AC: 94 AN: 53390

Middle Eastern (MID) AF: 0.0236 AC: 136 AN: 5768

European-Non Finnish (NFE) AF: 0.0120 AC: 13304 AN: 1111656

Other (OTH) AF: 0.0136 AC: 821 AN: 60364

GnomAD4 genome AF: 0.00877 AC: 1336 AN: 152334 Hom.: 13 Cov.: 32 AF XY: 0.00863 AC XY: 643 AN XY: 74486

African (AFR) AF: 0.00164 AC: 68 AN: 41586

American (AMR) AF: 0.00529 AC: 81 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4822

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 825 AN: 68018

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0126 Hom.: 16

Bravo AF: 0.00900

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17552682; hg19: chr5-73048819;