rs2973568

Variant names:

• chr5-73849020-A-G
• rs2973568
• NM_001177693.2:c.1680A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):​c.1680A>G​(p.Ser560Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,575,968 control chromosomes in the GnomAD database, including 282,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35574 hom., cov: 32)
  • Exomes 𝑓: 0.59 (247057 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.175
• Publications: 24 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-73849020-A-G is Benign according to our data. Variant chr5-73849020-A-G is described in ClinVar as Benign. ClinVar VariationId is 257359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.175 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.1680A>G	p.Ser560Ser	synonymous_variant	Exon 13 of 36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1680A>G	p.Ser560Ser	synonymous_variant	Exon 13 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101220 AN: 151854 Hom.: 35507 Cov.: 32

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.596 AC: 119906 AN: 201102 AF XY: 0.591

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.639

Gnomad ASJ exome AF: 0.584

Gnomad EAS exome AF: 0.523

Gnomad FIN exome AF: 0.524

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.585 AC: 833504 AN: 1423994 Hom.: 247057 Cov.: 41 AF XY: 0.584 AC XY: 411654 AN XY: 704906

African (AFR) AF: 0.916 AC: 30026 AN: 32794

American (AMR) AF: 0.637 AC: 25417 AN: 39872

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 14721 AN: 25556

East Asian (EAS) AF: 0.478 AC: 18441 AN: 38548

South Asian (SAS) AF: 0.613 AC: 49818 AN: 81226

European-Finnish (FIN) AF: 0.533 AC: 27304 AN: 51270

Middle Eastern (MID) AF: 0.643 AC: 3680 AN: 5724

European-Non Finnish (NFE) AF: 0.577 AC: 628775 AN: 1090016

Other (OTH) AF: 0.599 AC: 35322 AN: 58988

GnomAD4 genome AF: 0.667 AC: 101348 AN: 151974 Hom.: 35574 Cov.: 32 AF XY: 0.662 AC XY: 49124 AN XY: 74250

African (AFR) AF: 0.899 AC: 37320 AN: 41520

American (AMR) AF: 0.643 AC: 9812 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2003 AN: 3468

East Asian (EAS) AF: 0.522 AC: 2694 AN: 5162

South Asian (SAS) AF: 0.624 AC: 2997 AN: 4804

European-Finnish (FIN) AF: 0.522 AC: 5509 AN: 10544

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38785 AN: 67892

Other (OTH) AF: 0.657 AC: 1387 AN: 2110

Alfa AF: 0.608 Hom.: 48312

Bravo AF: 0.689

Asia WGS AF: 0.622 AC: 2159 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Benign	0.64
PhyloP100		0.17
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: rs2973568; hg19: chr5-73144845; COSMIC: COSV55249148;