rs3911730

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173630.4(RTTN):c.376T>G(p.Ser126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,611,712 control chromosomes in the GnomAD database, including 657,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S126T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.73 ( 47512 hom., cov: 31)

Exomes 𝑓: 0.91 ( 610305 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.16

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8645148E-6).

BP6

Variant 18-70204107-A-C is Benign according to our data. Variant chr18-70204107-A-C is described in ClinVar as [Benign]. Clinvar id is 130179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70204107-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4 linkuse as main transcript	c.376T>G	p.Ser126Ala	missense_variant	3/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2 linkuse as main transcript	c.376T>G	p.Ser126Ala	missense_variant	3/49	2	NM_173630.4	P1	Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111245

AN:

152040

Hom.:

47507

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.976

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.917

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.907

Gnomad FIN

AF:

0.910

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.771

GnomAD3 exomes

AF:

0.875

AC:

217592

AN:

248674

Hom.:

98767

AF XY:

0.887

AC XY:

119672

AN XY:

134912

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.875

Gnomad ASJ exome

AF:

0.914

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.906

Gnomad FIN exome

AF:

0.910

Gnomad NFE exome

AF:

0.924

Gnomad OTH exome

AF:

0.892

GnomAD4 exome

AF:

0.908

AC:

1325118

AN:

1459554

Hom.:

610305

Cov.:

AF XY:

0.910

AC XY:

660661

AN XY:

726178

show subpopulations

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.868

Gnomad4 ASJ exome

AF:

0.912

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.906

Gnomad4 FIN exome

AF:

0.911

Gnomad4 NFE exome

AF:

0.928

Gnomad4 OTH exome

AF:

0.879

GnomAD4 genome

AF:

0.731

AC:

111278

AN:

152158

Hom.:

47512

Cov.:

AF XY:

0.737

AC XY:

54863

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.253

Gnomad4 AMR

AF:

0.846

Gnomad4 ASJ

AF:

0.917

Gnomad4 EAS

AF:

0.997

Gnomad4 SAS

AF:

0.907

Gnomad4 FIN

AF:

0.910

Gnomad4 NFE

AF:

0.922

Gnomad4 OTH

AF:

0.774

Alfa

AF:

0.885

Hom.:

117635

Bravo

AF:

0.703

TwinsUK

AF:

0.928

AC:

3442

ALSPAC

AF:

0.931

AC:

3590

ESP6500AA

AF:

0.291

AC:

1071

ESP6500EA

AF:

0.924

AC:

7553

ExAC

AF:

0.865

AC:

104503

Asia WGS

AF:

0.897

AC:

3116

AN:

3478

EpiCase

AF:

0.923

EpiControl

AF:

0.924

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2017	- -

Microcephalic primordial dwarfism due to RTTN deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.15

DANN

Benign

0.78

DEOGEN2

Benign

0.053

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0000019

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.69

.;N

REVEL

Benign

0.061

Sift

Benign

0.70

.;T

Sift4G

Benign

0.83

.;T

Polyphen

0.0

B;.

Vest4

0.024

MPC

0.064

ClinPred

0.0039

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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