chr18-70166070-T-C

Position:

chr18-70166070-T-C

Variant summary

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

The NM_173630.4(RTTN):c.1921A>G(p.Ile641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,613,612 control chromosomes in the GnomAD database, including 93 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 0.0060 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 90 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.878

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=0.004217416).

BP6

Variant 18-70166070-T-C is Benign according to our data. Variant chr18-70166070-T-C is described in ClinVar as [Benign]. Clinvar id is 130168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00597 (909/152336) while in subpopulation NFE AF= 0.00924 (629/68038). AF 95% confidence interval is 0.00865. There are 3 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4 linkuse as main transcript	c.1921A>G	p.Ile641Val	missense_variant	14/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2 linkuse as main transcript	c.1921A>G	p.Ile641Val	missense_variant	14/49	2	NM_173630.4	P1	Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.00598

AC:

911

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00924

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00672

AC:

1673

AN:

248946

Hom.:

AF XY:

0.00723

AC XY:

977

AN XY:

135068

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00587

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0104

Gnomad FIN exome

AF:

0.00640

Gnomad NFE exome

AF:

0.00898

Gnomad OTH exome

AF:

0.00696

GnomAD4 exome

AF:

0.00931

AC:

13598

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

6761

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00597

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0100

Gnomad4 FIN exome

AF:

0.00685

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00919

GnomAD4 genome

AF:

0.00597

AC:

909

AN:

152336

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

445

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.00442

Gnomad4 NFE

AF:

0.00924

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00861

Hom.:

Bravo

AF:

0.00579

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00289

AC:

ESP6500EA

AF:

0.00933

AC:

ExAC

AF:

0.00675

AC:

816

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00999

EpiControl

AF:

0.00836

ClinVar

Significance: 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 submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RTTN: BP4, BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2018	- -

RTTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

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

0.087

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.0

DANN

Benign

0.92

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

.;N;.

REVEL

Benign

0.018

Sift

Benign

0.26

.;T;.

Sift4G

Benign

0.35

.;T;.

Polyphen

0.0040

B;.;.

Vest4

0.12

MVP

0.16

MPC

0.061

ClinPred

0.0012

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.11

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