18-70020730-C-A

Position:

chr18-70020730-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4 linkuse as main transcript	c.6038G>T	p.Cys2013Phe	missense_variant	45/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2 linkuse as main transcript	c.6038G>T	p.Cys2013Phe	missense_variant	45/49	2	NM_173630.4	P1	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

GnomAD3 exomes

AF:

0.00661

AC:

1646

AN:

248958

Hom.:

AF XY:

0.00741

AC XY:

1000

AN XY:

135028

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 SAS exome

AF:

0.0132

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

Gnomad4 AMR exome

AF:

0.00470

Gnomad4 ASJ exome

AF:

0.00459

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.00185

Gnomad4 NFE exome

AF:

0.00851

Gnomad4 OTH exome

AF:

0.00671

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

Gnomad4 AMR

AF:

0.00771

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00705

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00839

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00732

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RTTN: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2019

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

MutationTaster

Benign

0.54

D;N

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

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