NM_001177693.2:c.33+160G>C

Variant names:

• chr5-73685044-G-C
• rs10755296
• NM_001177693.2:c.33+160G>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.33+160G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 152,142 control chromosomes in the GnomAD database, including 38,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.71 (38677 hom., cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.149
• Publications: 9 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 (BayesDel_noAF=-0.77).
• BP6: Variant 5-73685044-G-C is Benign according to our data. Variant chr5-73685044-G-C is described in ClinVar as Benign. ClinVar VariationId is 1250963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 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.33+160G>C		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.33+160G>C		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.33+160G>C		intron	N/A	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.33+160G>C		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.33+160G>C		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.33+160G>C		intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108254 AN: 152024 Hom.: 38637 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.714

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

GnomAD4 genome AF: 0.712 AC: 108346 AN: 152142 Hom.: 38677 Cov.: 32 AF XY: 0.714 AC XY: 53129 AN XY: 74380

African (AFR) AF: 0.665 AC: 27590 AN: 41462

American (AMR) AF: 0.786 AC: 12016 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2375 AN: 3470

East Asian (EAS) AF: 0.819 AC: 4242 AN: 5180

South Asian (SAS) AF: 0.718 AC: 3460 AN: 4820

European-Finnish (FIN) AF: 0.748 AC: 7920 AN: 10592

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48426 AN: 68000

Other (OTH) AF: 0.711 AC: 1505 AN: 2116

Alfa AF: 0.642 Hom.: 1901

Bravo AF: 0.714

Asia WGS AF: 0.769 AC: 2674 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		0.15
PromoterAI		0.0013	Neutral
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: rs10755296; hg19: chr5-72980869;