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rs145976466

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173630.4(RTTN):c.6038G>T(p.Cys2013Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,614,080 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0079 ( 76 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

3
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.72
Variant links:
Genes affected
RTTN (HGNC:18654): (rotatin) This gene encodes a large protein whose specific function is unknown. Absence of the orthologous protein in mouse results in embryonic lethality with deficient axial rotation, abnormal differentiation of the neural tube, and randomized looping of the heart tube during development. In human, mutations in this gene are associated with polymicrogyria with seizures. In human fibroblasts this protein localizes at the ciliary basal bodies. Given the intracellular localization of this protein and the phenotypic effects of mutations, this gene is suspected of playing a role in the maintenance of normal ciliary structure which in turn effects the developmental process of left-right organ specification, axial rotation, and perhaps notochord development. [provided by RefSeq, Jan 2013]

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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=0.005443305).
BP6
Variant 18-70020730-C-A is Benign according to our data. Variant chr18-70020730-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 130190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70020730-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0054 (822/152344) while in subpopulation NFE AF= 0.00839 (571/68034). AF 95% confidence interval is 0.00782. There are 4 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RTTNNM_173630.4 linkuse as main transcriptc.6038G>T p.Cys2013Phe missense_variant 45/49 ENST00000640769.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RTTNENST00000640769.2 linkuse as main transcriptc.6038G>T p.Cys2013Phe missense_variant 45/492 NM_173630.4 P1Q86VV8-1

Frequencies

GnomAD3 genomes
AF:
0.00540
AC:
822
AN:
152226
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00116
Gnomad AMI
AF:
0.0197
Gnomad AMR
AF:
0.00778
Gnomad ASJ
AF:
0.00375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00704
Gnomad FIN
AF:
0.000942
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00839
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00661
AC:
1646
AN:
248958
Hom.:
17
AF XY:
0.00741
AC XY:
1000
AN XY:
135028
show subpopulations
Gnomad AFR exome
AF:
0.00103
Gnomad AMR exome
AF:
0.00449
Gnomad ASJ exome
AF:
0.00537
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0132
Gnomad FIN exome
AF:
0.00139
Gnomad NFE exome
AF:
0.00837
Gnomad OTH exome
AF:
0.00711
GnomAD4 exome
AF:
0.00793
AC:
11587
AN:
1461736
Hom.:
76
Cov.:
31
AF XY:
0.00807
AC XY:
5869
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00170
Gnomad4 AMR exome
AF:
0.00470
Gnomad4 ASJ exome
AF:
0.00459
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0129
Gnomad4 FIN exome
AF:
0.00185
Gnomad4 NFE exome
AF:
0.00851
Gnomad4 OTH exome
AF:
0.00671
GnomAD4 genome
AF:
0.00540
AC:
822
AN:
152344
Hom.:
4
Cov.:
32
AF XY:
0.00545
AC XY:
406
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00115
Gnomad4 AMR
AF:
0.00771
Gnomad4 ASJ
AF:
0.00375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00705
Gnomad4 FIN
AF:
0.000942
Gnomad4 NFE
AF:
0.00839
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00732
Hom.:
7
Bravo
AF:
0.00535
TwinsUK
AF:
0.00674
AC:
25
ALSPAC
AF:
0.0101
AC:
39
ESP6500AA
AF:
0.00129
AC:
5
ESP6500EA
AF:
0.00834
AC:
69
ExAC
AF:
0.00707
AC:
854
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.00917
EpiControl
AF:
0.00806

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023RTTN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 20, 2016- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 10, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 22, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
RTTN-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 18, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.29
Cadd
Benign
20
Dann
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.84
T;T;T
MetaRNN
Benign
0.0054
T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.9
M;.;M
MutationTaster
Benign
0.54
D;N
PrimateAI
Benign
0.31
T
Polyphen
0.99
D;.;.
Vest4
0.37
MVP
0.51
MPC
0.17
ClinPred
0.0078
T
GERP RS
6.1
Varity_R
0.13
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs145976466; hg19: chr18-67687966; COSMIC: COSV105050690; COSMIC: COSV105050690; API