chr5-73901264-G-A

Variant names:

• chr5-73901264-G-A
• rs188040167
• NM_001177693.2:c.4054G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001080479.3(ARHGEF28):​c.4054G>A​(p.Val1352Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,612,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (12 hom.)
• Consequence: ARHGEF28 NM_001080479.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.26
• Publications: 14 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 Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000304540 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044407547).
• BP6: Variant 5-73901264-G-A is Benign according to our data. Variant chr5-73901264-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080479.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.4054G>A	p.Val1352Ile	missense	Exon 31 of 36	NP_001171164.1
	ARHGEF28	NM_001080479.3		c.4054G>A	p.Val1352Ile	missense	Exon 31 of 37	NP_001073948.2
	ARHGEF28	NM_001388078.1		c.4054G>A	p.Val1352Ile	missense	Exon 31 of 35	NP_001375007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.4054G>A	p.Val1352Ile	missense	Exon 31 of 36	ENSP00000441436.1
	ARHGEF28	ENST00000437974.5	TSL:1	c.4054G>A	p.Val1352Ile	missense	Exon 30 of 36	ENSP00000411459.1
	ARHGEF28	ENST00000426542.6	TSL:1	c.4054G>A	p.Val1352Ile	missense	Exon 30 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00293 AC: 728 AN: 248556 AF XY: 0.00298

Gnomad AFR exome AF: 0.000843

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00400 AC: 5848 AN: 1460778 Hom.: 12 Cov.: 30 AF XY: 0.00399 AC XY: 2900 AN XY: 726628

African (AFR) AF: 0.000687 AC: 23 AN: 33470

American (AMR) AF: 0.00141 AC: 63 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00556 AC: 145 AN: 26098

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39664

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86026

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53332

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.00455 AC: 5056 AN: 1111416

Other (OTH) AF: 0.00393 AC: 237 AN: 60334

GnomAD4 genome AF: 0.00314 AC: 478 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74402

African (AFR) AF: 0.000892 AC: 37 AN: 41500

American (AMR) AF: 0.00438 AC: 67 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4814

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00376 Hom.: 3

Bravo AF: 0.00284

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00126 AC: 5

ESP6500EA AF: 0.00494 AC: 41

ExAC AF: 0.00304 AC: 367

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00380

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0091	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.070
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.23	B
Vest4		0.11
MVP		0.20
MPC		0.063
ClinPred		0.0068	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.058
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs188040167; hg19: chr5-73197089; COSMIC: COSV55262059;