chr5-73919412-G-A

Variant names:

• chr5-73919412-G-A
• rs16871023
• NM_001177693.2:c.4948+7837G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001177693.2(ARHGEF28):​c.4948+7837G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,154 control chromosomes in the GnomAD database, including 4,041 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (4041 hom., cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.79
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 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.4948+7837G>A		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.4949-3675G>A		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388076.1		c.4654+7837G>A		intron	N/A	NP_001375005.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.4948+7837G>A		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.4949-3675G>A		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.4948+7837G>A		intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24353 AN: 152036 Hom.: 4018 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0647

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.161 AC: 24425 AN: 152154 Hom.: 4041 Cov.: 32 AF XY: 0.156 AC XY: 11598 AN XY: 74390

African (AFR) AF: 0.418 AC: 17352 AN: 41464

American (AMR) AF: 0.154 AC: 2356 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3466

East Asian (EAS) AF: 0.0647 AC: 335 AN: 5178

South Asian (SAS) AF: 0.119 AC: 573 AN: 4830

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10610

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3108 AN: 67996

Other (OTH) AF: 0.137 AC: 290 AN: 2116

Alfa AF: 0.0789 Hom.: 3951

Bravo AF: 0.186

Asia WGS AF: 0.112 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.047
DANN	Benign	0.48
PhyloP100		-2.8
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: rs16871023; hg19: chr5-73215237;