rs115243197

Positions:

• chr5-73857727-G-A
• chr5-73857727-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001177693.2(ARHGEF28):​c.1862G>A​(p.Arg621Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,612,418 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (69 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.56

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069202185).
• BP6: Variant 5-73857727-G-A is Benign according to our data. Variant chr5-73857727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.1862G>A	p.Arg621Gln	missense_variant	15/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1862G>A	p.Arg621Gln	missense_variant	15/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 152004 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00680 AC: 1682 AN: 247172 Hom.: 21 AF XY: 0.00710 AC XY: 952 AN XY: 134102

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.00670

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00702 AC: 10246 AN: 1460296 Hom.: 69 Cov.: 31 AF XY: 0.00694 AC XY: 5038 AN XY: 726350

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.000958

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00408

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.00708

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.00648 AC: 985 AN: 152122 Hom.: 8 Cov.: 32 AF XY: 0.00800 AC XY: 595 AN XY: 74372

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.00668

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00659 Hom.: 4

Bravo AF: 0.00404

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00808 AC: 66

ExAC AF: 0.00667 AC: 805

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ARHGEF28: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;.;T;.;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;.;.;D
MetaRNN	Benign	0.0069	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.64
MVP		0.43
MPC		0.45
ClinPred		0.053	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs115243197; hg19: chr5-73153552; COSMIC: COSV55247896;