rs2973558

Variant names:

• chr5-73868140-C-A
• rs2973558
• NM_001177693.2:c.2338C>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.2338C>A​(p.His780Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,607,836 control chromosomes in the GnomAD database, including 80,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6596 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73959 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.160
• Publications: 30 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 (MetaRNN=2.4458766E-4).
• BP6: Variant 5-73868140-C-A is Benign according to our data. Variant chr5-73868140-C-A is described in ClinVar as Benign. ClinVar VariationId is 257364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.378 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.2338C>A	p.His780Asn	missense	Exon 20 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.2338C>A	p.His780Asn	missense	Exon 20 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.2338C>A	p.His780Asn	missense	Exon 20 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.2338C>A	p.His780Asn	missense	Exon 20 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.2338C>A	p.His780Asn	missense	Exon 19 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.2338C>A	p.His780Asn	missense	Exon 19 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43360 AN: 151954 Hom.: 6587 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.299 AC: 71577 AN: 239616 AF XY: 0.290

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.314 AC: 457341 AN: 1455762 Hom.: 73959 Cov.: 38 AF XY: 0.310 AC XY: 223952 AN XY: 723452

African (AFR) AF: 0.203 AC: 6785 AN: 33438

American (AMR) AF: 0.448 AC: 19581 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 7660 AN: 25990

East Asian (EAS) AF: 0.116 AC: 4572 AN: 39550

South Asian (SAS) AF: 0.200 AC: 17043 AN: 85190

European-Finnish (FIN) AF: 0.298 AC: 15825 AN: 53052

Middle Eastern (MID) AF: 0.265 AC: 1517 AN: 5732

European-Non Finnish (NFE) AF: 0.330 AC: 366361 AN: 1108950

Other (OTH) AF: 0.299 AC: 17997 AN: 60168

GnomAD4 genome AF: 0.285 AC: 43398 AN: 152074 Hom.: 6596 Cov.: 32 AF XY: 0.280 AC XY: 20850 AN XY: 74342

African (AFR) AF: 0.210 AC: 8694 AN: 41480

American (AMR) AF: 0.387 AC: 5908 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3472

East Asian (EAS) AF: 0.138 AC: 714 AN: 5176

South Asian (SAS) AF: 0.196 AC: 945 AN: 4814

European-Finnish (FIN) AF: 0.294 AC: 3102 AN: 10564

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22005 AN: 67966

Other (OTH) AF: 0.281 AC: 593 AN: 2114

Alfa AF: 0.306 Hom.: 27739

Bravo AF: 0.292

TwinsUK AF: 0.338 AC: 1254

ALSPAC AF: 0.336 AC: 1295

ESP6500AA AF: 0.202 AC: 792

ESP6500EA AF: 0.311 AC: 2584

ExAC AF: 0.285 AC: 34448

Asia WGS AF: 0.156 AC: 544 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.0
DANN	Benign	0.79
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.16
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.032
Sift	Benign	0.14	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.033
MPC		0.076
ClinPred		0.0057	T
GERP RS		-0.56
Varity_R		0.046
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2973558; hg19: chr5-73163965; COSMIC: COSV55257053; COSMIC: COSV55257053;