rs1478453

Variant names:

• chr5-73911547-T-A
• rs1478453
• NM_001177693.2:c.4920T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-73911547-T-A
• chr5-73911547-T-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.4920T>A​(p.His1640Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,607,754 control chromosomes in the GnomAD database, including 114,467 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10389 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104078 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.484
• Publications: 29 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

ENSG00000304540 (HGNC:59068):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.567172E-4).
• BP6: Variant 5-73911547-T-A is Benign according to our data. Variant chr5-73911547-T-A is described in ClinVar as Benign. ClinVar VariationId is 257374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 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.4920T>A	p.His1640Gln	missense	Exon 35 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.4920T>A	p.His1640Gln	missense	Exon 35 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.4920T>A	p.His1640Gln	missense	Exon 35 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.4920T>A	p.His1640Gln	missense	Exon 35 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.4920T>A	p.His1640Gln	missense	Exon 34 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.4920T>A	p.His1640Gln	missense	Exon 34 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55546 AN: 151978 Hom.: 10373 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.330 AC: 79122 AN: 240052 AF XY: 0.331

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.372 AC: 541640 AN: 1455656 Hom.: 104078 Cov.: 42 AF XY: 0.368 AC XY: 266181 AN XY: 723240

African (AFR) AF: 0.372 AC: 12421 AN: 33422

American (AMR) AF: 0.200 AC: 8803 AN: 43940

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12511 AN: 25984

East Asian (EAS) AF: 0.206 AC: 8149 AN: 39612

South Asian (SAS) AF: 0.207 AC: 17665 AN: 85304

European-Finnish (FIN) AF: 0.343 AC: 18223 AN: 53192

Middle Eastern (MID) AF: 0.326 AC: 1878 AN: 5758

European-Non Finnish (NFE) AF: 0.397 AC: 439709 AN: 1108260

Other (OTH) AF: 0.370 AC: 22281 AN: 60184

GnomAD4 genome AF: 0.365 AC: 55590 AN: 152098 Hom.: 10389 Cov.: 32 AF XY: 0.358 AC XY: 26620 AN XY: 74356

African (AFR) AF: 0.377 AC: 15642 AN: 41478

American (AMR) AF: 0.274 AC: 4192 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1642 AN: 3466

East Asian (EAS) AF: 0.225 AC: 1167 AN: 5180

South Asian (SAS) AF: 0.206 AC: 996 AN: 4824

European-Finnish (FIN) AF: 0.343 AC: 3626 AN: 10566

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27140 AN: 67980

Other (OTH) AF: 0.346 AC: 731 AN: 2112

Alfa AF: 0.394 Hom.: 9232

Bravo AF: 0.363

TwinsUK AF: 0.398 AC: 1476

ALSPAC AF: 0.397 AC: 1531

ESP6500AA AF: 0.359 AC: 1490

ESP6500EA AF: 0.398 AC: 3351

ExAC AF: 0.331 AC: 40010

Asia WGS AF: 0.242 AC: 843 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	0.080
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.10
DANN	Benign	0.48
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00026	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.48
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.021
Sift	Benign	0.58	T
Sift4G	Benign	0.47	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.045		Gain of phosphorylation at S1642 (P = 0.2469)
MPC		0.071
ClinPred		0.0012	T
GERP RS		-1.8
Varity_R		0.027
gMVP		0.13
Mutation Taster		=99/1	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: rs1478453; hg19: chr5-73207372; COSMIC: COSV55269622;