rs2973548

Variant names:

• chr5-73795403-C-T
• rs2973548
• NM_001177693.2:c.1024+12C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-73795403-C-T
• chr5-73795403-C-A

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.1024+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,607,310 control chromosomes in the GnomAD database, including 167,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13146 hom., cov: 31)
  • Exomes 𝑓: 0.46 (154249 hom.)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.86
• Publications: 8 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=-0.95).
• BP6: Variant 5-73795403-C-T is Benign according to our data. Variant chr5-73795403-C-T is described in ClinVar as Benign. ClinVar VariationId is 257357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 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.1024+12C>T		intron	N/A	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.1024+12C>T		intron	N/A	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.1024+12C>T		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.1024+12C>T		intron	N/A	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.1024+12C>T		intron	N/A	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.1024+12C>T		intron	N/A	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62068 AN: 151812 Hom.: 13137 Cov.: 31

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.402

GnomAD2 exomes AF: 0.429 AC: 106721 AN: 248586 AF XY: 0.430

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.277

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.457 AC: 664962 AN: 1455378 Hom.: 154249 Cov.: 32 AF XY: 0.455 AC XY: 329559 AN XY: 724346

African (AFR) AF: 0.304 AC: 10139 AN: 33328

American (AMR) AF: 0.421 AC: 18786 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10394 AN: 26088

East Asian (EAS) AF: 0.260 AC: 10321 AN: 39644

South Asian (SAS) AF: 0.394 AC: 33870 AN: 85980

European-Finnish (FIN) AF: 0.494 AC: 26357 AN: 53362

Middle Eastern (MID) AF: 0.397 AC: 2289 AN: 5760

European-Non Finnish (NFE) AF: 0.476 AC: 526567 AN: 1106408

Other (OTH) AF: 0.436 AC: 26239 AN: 60174

GnomAD4 genome AF: 0.409 AC: 62102 AN: 151932 Hom.: 13146 Cov.: 31 AF XY: 0.408 AC XY: 30319 AN XY: 74246

African (AFR) AF: 0.312 AC: 12929 AN: 41432

American (AMR) AF: 0.404 AC: 6163 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1365 AN: 3468

East Asian (EAS) AF: 0.277 AC: 1432 AN: 5170

South Asian (SAS) AF: 0.396 AC: 1905 AN: 4814

European-Finnish (FIN) AF: 0.492 AC: 5173 AN: 10520

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31701 AN: 67940

Other (OTH) AF: 0.405 AC: 856 AN: 2112

Alfa AF: 0.432 Hom.: 9190

Bravo AF: 0.399

Asia WGS AF: 0.307 AC: 1069 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	-0.95
CADD	Benign	0.13
DANN	Benign	0.47
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs2973548; hg19: chr5-73091228; COSMIC: COSV55250862;