rs10473959

Variant names:

• chr5-73776679-A-C
• rs10473959
• NM_001177693.2:c.823A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000513042.7(ARHGEF28):​c.823A>C​(p.Arg275Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,613,052 control chromosomes in the GnomAD database, including 1,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (188 hom., cov: 32)
  • Exomes 𝑓: 0.031 (882 hom.)
• Consequence: ARHGEF28 ENST00000513042.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.58
• 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 Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-73776679-A-C is Benign according to our data. Variant chr5-73776679-A-C is described in ClinVar as Benign. ClinVar VariationId is 257377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000513042.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.823A>C	p.Arg275Arg	synonymous	Exon 6 of 36	NP_001171164.1
	ARHGEF28	NM_001080479.3		c.823A>C	p.Arg275Arg	synonymous	Exon 6 of 37	NP_001073948.2
	ARHGEF28	NM_001388078.1		c.823A>C	p.Arg275Arg	synonymous	Exon 6 of 35	NP_001375007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.823A>C	p.Arg275Arg	synonymous	Exon 6 of 36	ENSP00000441436.1
	ARHGEF28	ENST00000437974.5	TSL:1	c.823A>C	p.Arg275Arg	synonymous	Exon 5 of 36	ENSP00000411459.1
	ARHGEF28	ENST00000426542.6	TSL:1	c.823A>C	p.Arg275Arg	synonymous	Exon 5 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6891 AN: 152138 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0325 AC: 8088 AN: 248806 AF XY: 0.0323

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0311 AC: 45496 AN: 1460798 Hom.: 882 Cov.: 32 AF XY: 0.0314 AC XY: 22824 AN XY: 726686

African (AFR) AF: 0.0842 AC: 2819 AN: 33466

American (AMR) AF: 0.0211 AC: 941 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 729 AN: 26100

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0355 AC: 3051 AN: 86064

European-Finnish (FIN) AF: 0.0488 AC: 2602 AN: 53360

Middle Eastern (MID) AF: 0.0383 AC: 221 AN: 5768

European-Non Finnish (NFE) AF: 0.0300 AC: 33332 AN: 1111326

Other (OTH) AF: 0.0298 AC: 1798 AN: 60316

GnomAD4 genome AF: 0.0454 AC: 6907 AN: 152254 Hom.: 188 Cov.: 32 AF XY: 0.0461 AC XY: 3434 AN XY: 74446

African (AFR) AF: 0.0816 AC: 3390 AN: 41538

American (AMR) AF: 0.0239 AC: 365 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4824

European-Finnish (FIN) AF: 0.0522 AC: 554 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2198 AN: 68020

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0349 Hom.: 290

Bravo AF: 0.0447

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Benign	0.76
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs10473959; hg19: chr5-73072504;