chr18-70051452-A-G

Position:

chr18-70051452-A-G

Variant summary

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

The NM_173630.4(RTTN):c.5282T>C(p.Phe1761Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,613,786 control chromosomes in the GnomAD database, including 717,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 53926 hom., cov: 33)

Exomes 𝑓: 0.95 ( 663174 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.01

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=7.268011E-7).

BP6

Variant 18-70051452-A-G is Benign according to our data. Variant chr18-70051452-A-G is described in ClinVar as [Benign]. Clinvar id is 130188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70051452-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4 linkuse as main transcript	c.5282T>C	p.Phe1761Ser	missense_variant	39/49	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2 linkuse as main transcript	c.5282T>C	p.Phe1761Ser	missense_variant	39/49	2	NM_173630.4	ENSP00000491507	P1	Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.807

AC:

122676

AN:

152072

Hom.:

53904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.894

Gnomad AMR

AF:

0.907

Gnomad ASJ

AF:

0.954

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.966

Gnomad FIN

AF:

0.960

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.959

Gnomad OTH

AF:

0.841

GnomAD3 exomes

AF:

0.927

AC:

231014

AN:

249198

Hom.:

109410

AF XY:

0.936

AC XY:

126583

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.947

Gnomad ASJ exome

AF:

0.956

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.964

Gnomad FIN exome

AF:

0.959

Gnomad NFE exome

AF:

0.961

Gnomad OTH exome

AF:

0.939

GnomAD4 exome

AF:

0.949

AC:

1386540

AN:

1461596

Hom.:

663174

Cov.:

AF XY:

0.951

AC XY:

691320

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.403

Gnomad4 AMR exome

AF:

0.942

Gnomad4 ASJ exome

AF:

0.955

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.963

Gnomad4 FIN exome

AF:

0.960

Gnomad4 NFE exome

AF:

0.963

Gnomad4 OTH exome

AF:

0.927

GnomAD4 genome

AF:

0.807

AC:

122742

AN:

152190

Hom.:

53926

Cov.:

AF XY:

0.812

AC XY:

60422

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.420

Gnomad4 AMR

AF:

0.907

Gnomad4 ASJ

AF:

0.954

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.967

Gnomad4 FIN

AF:

0.960

Gnomad4 NFE

AF:

0.959

Gnomad4 OTH

AF:

0.843

Alfa

AF:

0.934

Hom.:

162916

Bravo

AF:

0.783

TwinsUK

AF:

0.960

AC:

3558

ALSPAC

AF:

0.969

AC:

3733

ESP6500AA

AF:

0.458

AC:

1758

ESP6500EA

AF:

0.962

AC:

7961

ExAC

AF:

0.918

AC:

110917

Asia WGS

AF:

0.941

AC:

3271

AN:

3478

EpiCase

AF:

0.959

EpiControl

AF:

0.960

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephalic primordial dwarfism due to RTTN deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.025

DANN

Benign

0.58

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

2.2

.;N

REVEL

Benign

0.018

Sift

Benign

0.98

.;T

Sift4G

Benign

0.67

.;T

Polyphen

0.0

B;.

Vest4

0.012

MPC

0.12

ClinPred

0.0067

GERP RS

-1.2

Varity_R

0.048

gMVP

0.15

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