5-73909872-C-G

Position:

• chr5-73909872-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001177693.2(ARHGEF28):​c.4622C>G​(p.Ala1541Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,520,832 control chromosomes in the GnomAD database, including 1,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (124 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1103 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.353

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027357042).
• BP6: Variant 5-73909872-C-G is Benign according to our data. Variant chr5-73909872-C-G is described in ClinVar as [Benign]. Clinvar id is 257372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73909872-C-G is described in Lovd as [Benign]. Variant chr5-73909872-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.4622C>G	p.Ala1541Gly	missense_variant	34/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4622C>G	p.Ala1541Gly	missense_variant	34/36	5	NM_001177693.2	ENSP00000441436

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6020 AN: 152066 Hom.: 124 Cov.: 31

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0341 AC: 4985 AN: 146130 Hom.: 110 AF XY: 0.0360 AC XY: 2905 AN XY: 80636

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.00930

Gnomad EAS exome AF: 0.0000689

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0549

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0426

GnomAD4 exome AF: 0.0376 AC: 51508 AN: 1368648 Hom.: 1103 Cov.: 30 AF XY: 0.0384 AC XY: 25891 AN XY: 674736

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.0250

Gnomad4 ASJ exome AF: 0.00985

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0589

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0396 AC: 6022 AN: 152184 Hom.: 124 Cov.: 31 AF XY: 0.0421 AC XY: 3129 AN XY: 74404

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0603

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0205 Hom.: 16

Bravo AF: 0.0373

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0277 AC: 92

ESP6500EA AF: 0.0244 AC: 182

ExAC AF: 0.0327 AC: 3791

Asia WGS AF: 0.0300 AC: 106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0038	.;.;T;.;T;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.87	D;D;D;.;.;D;D
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.094	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.16	B;.;B;.;B;.;D
Vest4		0.19
MPC		0.26
ClinPred		0.0064	T
GERP RS		3.4
Varity_R		0.025
gMVP		0.21

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: rs78992879; hg19: chr5-73205697; COSMIC: COSV104383008; COSMIC: COSV104383008;