chr5-73923129-C-T

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

1
15

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]

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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
ARHGEF28NM_001177693.2 linkc.4948+11554C>T intron_variant Intron 35 of 35 ENST00000513042.7 NP_001171164.1 Q8N1W1-1
ARHGEF28NM_001080479.3 linkc.4991C>T p.Pro1664Leu missense_variant Exon 36 of 37 NP_001073948.2 Q8N1W1-6
ARHGEF28NM_001388076.1 linkc.4654+11554C>T intron_variant Intron 34 of 34 NP_001375005.1
ARHGEF28NM_001244364.2 linkc.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
ARHGEF28ENST00000513042.7 linkc.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.:
32
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.:
32
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.:
32
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
T
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
N
LIST_S2
Benign
0.48
T;.;T
MetaRNN
Benign
0.000044
T;T;T
MetaSVM
Benign
-0.91
T
PrimateAI
Benign
0.17
T
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
T
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.

Other links and lift over

dbSNP: rs423333; hg19: chr5-73218954; COSMIC: COSV55249161; API