rs34989098

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173630.4(RTTN):c.6445G>A(p.Ala2149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,800 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 63 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.376

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00667727).

BP6

Variant 18-70006461-C-T is Benign according to our data. Variant chr18-70006461-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00609 (927/152336) while in subpopulation AMR AF= 0.00921 (141/15304). AF 95% confidence interval is 0.00846. There are 5 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4 link	c.6445G>A	p.Ala2149Thr	missense_variant	Exon 47 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.6445G>A	p.Ala2149Thr	missense_variant	Exon 47 of 49	2	NM_173630.4	ENSP00000491507.1		Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.00608

AC:

926

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00904

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00577

AC:

1438

AN:

249042

Hom.:

AF XY:

0.00604

AC XY:

816

AN XY:

135086

show subpopulations

Gnomad AFR exome

AF:

0.000840

Gnomad AMR exome

AF:

0.00417

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00941

Gnomad NFE exome

AF:

0.00853

Gnomad OTH exome

AF:

0.00579

GnomAD4 exome

AF:

0.00621

AC:

9077

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

4587

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00472

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.00968

Gnomad4 NFE exome

AF:

0.00699

Gnomad4 OTH exome

AF:

0.00533

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152336

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

439

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00921

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00838

Gnomad4 NFE

AF:

0.00905

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00743

Hom.:

Bravo

AF:

0.00557

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000815

AC:

ESP6500EA

AF:

0.00808

AC:

ExAC

AF:

0.00571

AC:

690

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTTN: BP4, BS2 -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephalic primordial dwarfism due to RTTN deficiency

Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Possible pathogenicity based on finding it once in our laboratory in trans with another missense variant in a 3-year-old female with microcephaly, craniosynostosis, dysmorphisms, fused labia, absence seizures, failure to thrive. However, allele frequency is high, and homozygotes have been found in controls. -

not specified

Benign:1

May 05, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RTTN-related disorder

Benign:1

Sep 12, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.9

DANN

Benign

0.87

DEOGEN2

Benign

0.022

T;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

0.050

.;.;N

REVEL

Benign

0.059

Sift

Benign

0.64

.;.;T

Sift4G

Benign

0.89

.;.;T

Polyphen

0.0010

B;.;.

Vest4

0.095

MVP

0.095

MPC

0.068

ClinPred

0.0043

GERP RS

1.1

Varity_R

0.034

gMVP

0.043

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