chr5-73923129-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001080479.3(ARHGEF28):c.4991C>T(p.Pro1664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,534,866 control chromosomes in the GnomAD database, including 36,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1664P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 7666 hom., cov: 32)

Exomes 𝑓: 0.19 ( 28844 hom. )

Consequence

ARHGEF28
NM_001080479.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.4029228E-5).

BP6

Variant 5-73923129-C-T is Benign according to our data. Variant chr5-73923129-C-T is described in ClinVar as [Benign]. Clinvar id is 257375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73923129-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.4948+11554C>T		intron_variant	Intron 35 of 35	ENST00000513042.7	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3 link	c.4991C>T	p.Pro1664Leu	missense_variant	Exon 36 of 37		NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388076.1 link	c.4654+11554C>T		intron_variant	Intron 34 of 34		NP_001375005.1
ARHGEF28	NM_001244364.2 link	c.4009+11554C>T		intron_variant	Intron 27 of 27		NP_001231293.1	Q8N1W1-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.4948+11554C>T		intron_variant	Intron 35 of 35	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42216

AN:

151816

Hom.:

7641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.506

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.225

GnomAD3 exomes

AF:

0.246

AC:

33596

AN:

136596

Hom.:

5281

AF XY:

0.239

AC XY:

17770

AN XY:

74290

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.118

Gnomad SAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.190

AC:

263266

AN:

1382932

Hom.:

28844

Cov.:

AF XY:

0.193

AC XY:

131438

AN XY:

682408

show subpopulations

Gnomad4 AFR exome

AF:

0.512

Gnomad4 AMR exome

AF:

0.393

Gnomad4 ASJ exome

AF:

0.136

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.313

Gnomad4 FIN exome

AF:

0.161

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.193

GnomAD4 genome

AF:

0.278

AC:

42306

AN:

151934

Hom.:

7666

Cov.:

AF XY:

0.276

AC XY:

20498

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.506

Gnomad4 AMR

AF:

0.323

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.125

Gnomad4 SAS

AF:

0.329

Gnomad4 FIN

AF:

0.162

Gnomad4 NFE

AF:

0.167

Gnomad4 OTH

AF:

0.232

Alfa

AF:

0.181

Hom.:

6836

Bravo

AF:

0.299

TwinsUK

AF:

0.166

AC:

614

ALSPAC

AF:

0.165

AC:

634

ExAC

AF:

0.232

AC:

4005

Asia WGS

AF:

0.259

AC:

900

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Clinical Genetics, Academic 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

- -

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_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.37

DANN

Benign

0.42

DEOGEN2

Benign

0.0067

.;.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.48

T;.;T

MetaRNN

Benign

0.000044

T;T;T

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.46

N;N;N

REVEL

Benign

0.0070

Sift

Benign

1.0

T;T;T

Sift4G

Uncertain

0.053

T;T;D

Polyphen

0.0

.;.;B

Vest4

0.058

MPC

0.071

ClinPred

0.00072

GERP RS

-6.6

gMVP

0.072

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over