rs73118524

Variant names:

• chr5-73795324-C-T
• rs73118524
• NM_001177693.2:c.964-7C>T

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.964-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,612,788 control chromosomes in the GnomAD database, including 14,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5359 hom., cov: 32)
  • Exomes 𝑓: 0.075 (8791 hom.)
• Consequence: ARHGEF28 NM_001177693.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003687
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.691
• Publications: 6 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=-0.9).
• BP6: Variant 5-73795324-C-T is Benign according to our data. Variant chr5-73795324-C-T is described in ClinVar as Benign. ClinVar VariationId is 257380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 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.964-7C>T		splice_region intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.964-7C>T		splice_region intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.964-7C>T		splice_region 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.964-7C>T		splice_region intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.964-7C>T		splice_region intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.964-7C>T		splice_region intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28698 AN: 151998 Hom.: 5343 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.122 AC: 30264 AN: 248858 AF XY: 0.113

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.255

Gnomad FIN exome AF: 0.0573

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0746 AC: 109025 AN: 1460672 Hom.: 8791 Cov.: 34 AF XY: 0.0753 AC XY: 54730 AN XY: 726672

African (AFR) AF: 0.490 AC: 16352 AN: 33386

American (AMR) AF: 0.164 AC: 7321 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 1045 AN: 26124

East Asian (EAS) AF: 0.222 AC: 8816 AN: 39670

South Asian (SAS) AF: 0.159 AC: 13675 AN: 86140

European-Finnish (FIN) AF: 0.0552 AC: 2944 AN: 53376

Middle Eastern (MID) AF: 0.0909 AC: 524 AN: 5766

European-Non Finnish (NFE) AF: 0.0471 AC: 52392 AN: 1111220

Other (OTH) AF: 0.0987 AC: 5956 AN: 60342

GnomAD4 genome AF: 0.189 AC: 28765 AN: 152116 Hom.: 5359 Cov.: 32 AF XY: 0.189 AC XY: 14062 AN XY: 74392

African (AFR) AF: 0.479 AC: 19854 AN: 41440

American (AMR) AF: 0.153 AC: 2340 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1243 AN: 5176

South Asian (SAS) AF: 0.168 AC: 808 AN: 4820

European-Finnish (FIN) AF: 0.0563 AC: 596 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0490 AC: 3335 AN: 68014

Other (OTH) AF: 0.159 AC: 335 AN: 2110

Alfa AF: 0.110 Hom.: 1149

Bravo AF: 0.210

Asia WGS AF: 0.258 AC: 896 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.35
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs73118524; hg19: chr5-73091149; COSMIC: COSV55247714;