NM_001177693.2:c.4622C>G

Variant names:

• chr5-73909872-C-G
• rs78992879
• NM_001177693.2:c.4622C>G

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.4622C>G​(p.Ala1541Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,520,832 control chromosomes in the GnomAD database, including 1,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1541A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (124 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1103 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.353
• 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

ENSG00000304540 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027357042).
• BP6: Variant 5-73909872-C-G is Benign according to our data. Variant chr5-73909872-C-G is described in ClinVar as Benign. ClinVar VariationId is 257372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 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.4622C>G	p.Ala1541Gly	missense	Exon 34 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.4622C>G	p.Ala1541Gly	missense	Exon 34 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.4622C>G	p.Ala1541Gly	missense	Exon 34 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.4622C>G	p.Ala1541Gly	missense	Exon 34 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.4622C>G	p.Ala1541Gly	missense	Exon 33 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.4622C>G	p.Ala1541Gly	missense	Exon 33 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6020 AN: 152066 Hom.: 124 Cov.: 31

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0341 AC: 4985 AN: 146130 AF XY: 0.0360

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.00930

Gnomad EAS exome AF: 0.0000689

Gnomad FIN exome AF: 0.0549

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0426

GnomAD4 exome AF: 0.0376 AC: 51508 AN: 1368648 Hom.: 1103 Cov.: 30 AF XY: 0.0384 AC XY: 25891 AN XY: 674736

African (AFR) AF: 0.0462 AC: 1410 AN: 30500

American (AMR) AF: 0.0250 AC: 769 AN: 30802

Ashkenazi Jewish (ASJ) AF: 0.00985 AC: 206 AN: 20910

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38938

South Asian (SAS) AF: 0.0589 AC: 4236 AN: 71966

European-Finnish (FIN) AF: 0.0566 AC: 1973 AN: 34840

Middle Eastern (MID) AF: 0.0373 AC: 155 AN: 4154

European-Non Finnish (NFE) AF: 0.0377 AC: 40746 AN: 1080044

Other (OTH) AF: 0.0356 AC: 2009 AN: 56494

GnomAD4 genome AF: 0.0396 AC: 6022 AN: 152184 Hom.: 124 Cov.: 31 AF XY: 0.0421 AC XY: 3129 AN XY: 74404

African (AFR) AF: 0.0443 AC: 1840 AN: 41524

American (AMR) AF: 0.0328 AC: 502 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4828

European-Finnish (FIN) AF: 0.0626 AC: 664 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0381 AC: 2589 AN: 67998

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0205 Hom.: 16

Bravo AF: 0.0373

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0277 AC: 92

ESP6500EA AF: 0.0244 AC: 182

ExAC AF: 0.0327 AC: 3791

Asia WGS AF: 0.0300 AC: 106 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.35
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.036
Sift	Benign	0.094	T
Sift4G	Benign	0.26	T
Polyphen		0.16	B
Vest4		0.19
MPC		0.26
ClinPred		0.0064	T
GERP RS		3.4
Varity_R		0.025
gMVP		0.21
Mutation Taster		=95/5	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: rs78992879; hg19: chr5-73205697; COSMIC: COSV104383008;