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GeneBe

5-73753042-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001177693.2(ARHGEF28):c.315G>T(p.Thr105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,609,856 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0062 ( 61 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0300
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 -17 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-73753042-G-T is Benign according to our data. Variant chr5-73753042-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 257367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73753042-G-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.03 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ARHGEF28NM_001177693.2 linkuse as main transcriptc.315G>T p.Thr105= synonymous_variant 4/36 ENST00000513042.7
ARHGEF28NM_001080479.3 linkuse as main transcriptc.315G>T p.Thr105= synonymous_variant 4/37
ARHGEF28NM_001388078.1 linkuse as main transcriptc.315G>T p.Thr105= synonymous_variant 4/35
ARHGEF28NM_001388076.1 linkuse as main transcriptc.181+3058G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARHGEF28ENST00000513042.7 linkuse as main transcriptc.315G>T p.Thr105= synonymous_variant 4/365 NM_001177693.2 Q8N1W1-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00349
AC:
531
AN:
152170
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000869
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00667
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00335
AC:
804
AN:
239938
Hom.:
5
AF XY:
0.00342
AC XY:
445
AN XY:
130288
show subpopulations
Gnomad AFR exome
AF:
0.000903
Gnomad AMR exome
AF:
0.000986
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000339
Gnomad FIN exome
AF:
0.000954
Gnomad NFE exome
AF:
0.00663
Gnomad OTH exome
AF:
0.00307
GnomAD4 exome
AF:
0.00624
AC:
9091
AN:
1457568
Hom.:
61
Cov.:
31
AF XY:
0.00594
AC XY:
4302
AN XY:
724664
show subpopulations
Gnomad4 AFR exome
AF:
0.000988
Gnomad4 AMR exome
AF:
0.000930
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000820
Gnomad4 FIN exome
AF:
0.00117
Gnomad4 NFE exome
AF:
0.00772
Gnomad4 OTH exome
AF:
0.00608
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00349
AC:
532
AN:
152288
Hom.:
3
Cov.:
32
AF XY:
0.00303
AC XY:
226
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.000866
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00668
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00201
Hom.:
0
Bravo
AF:
0.00352
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
Cadd
Benign
1.8
Dann
Benign
0.44
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs191563093; hg19: chr5-73048867; API