18-70020730-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2013Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 76 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

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]

RTTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4 link	c.6038G>T	p.Cys2013Phe	missense_variant	Exon 45 of 49	ENST00000640769.2	NP_775901.3	Q86VV8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2 link	c.6038G>T	p.Cys2013Phe	missense_variant	Exon 45 of 49	2	NM_173630.4	ENSP00000491507.1		Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.00540

AC:

822

AN:

152226

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00661

AC:

1646

AN:

248958

AF XY:

0.00741

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 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.:

Cov.:

AF XY:

0.00807

AC XY:

5869

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.00470

AC:

210

AN:

44714

Gnomad4 ASJ exome

AF:

0.00459

AC:

120

AN:

26130

Gnomad4 EAS exome

AF:

0.0000504

AC:

AN:

39694

Gnomad4 SAS exome

AF:

0.0129

AC:

1112

AN:

86256

Gnomad4 FIN exome

AF:

0.00185

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00851

AC:

9463

AN:

1111884

Gnomad4 Remaining exome

AF:

0.00671

AC:

405

AN:

60394

Heterozygous variant carriers

575

1150

1726

2301

2876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00540

AC:

822

AN:

152344

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

406

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00115

AC:

0.00115462

AN:

0.00115462

Gnomad4 AMR

AF:

0.00771

AC:

0.00770537

AN:

0.00770537

Gnomad4 ASJ

AF:

0.00375

AC:

0.0037464

AN:

0.0037464

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00705

AC:

0.00704809

AN:

0.00704809

Gnomad4 FIN

AF:

0.000942

AC:

0.000941974

AN:

0.000941974

Gnomad4 NFE

AF:

0.00839

AC:

0.00839286

AN:

0.00839286

Gnomad4 OTH

AF:

0.00426

AC:

0.00425733

AN:

0.00425733

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00724

Hom.:

Bravo

AF:

0.00535

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00129

AC:

ESP6500EA

AF:

0.00834

AC:

ExAC

AF:

0.00707

AC:

854

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00917

EpiControl

AF:

0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 20, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTTN: BP4, BS1, BS2 -

not specified

Benign:2

Aug 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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 disorder

Benign:1

Apr 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This 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

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.9

M;.;M

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

.;.;N

REVEL

Benign

0.17

Sift

Benign

0.030

.;.;D

Sift4G

Uncertain

0.032

.;.;D

Polyphen

0.99

D;.;.

Vest4

0.37

MVP

0.51

MPC

0.17

ClinPred

0.0078

GERP RS

6.1

Varity_R

0.13

gMVP

0.31

Mutation Taster

=95/5

polymorphism

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.

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