rs145976466

chr18-70020730-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (76 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.72

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]

ACMG classification

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	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	c.6038G>T	p.Cys2013Phe	missense_variant	45/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 822 AN: 152226 Hom.: 4 Cov.: 32

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.: 17 AF XY: 0.00741 AC XY: 1000 AN XY: 135028

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.: 76 Cov.: 31 AF XY: 0.00807 AC XY: 5869 AN XY: 727192

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.: 4 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74508

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.: 7

Bravo AF: 0.00535

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.00834 AC: 69

ExAC AF: 0.00707 AC: 854

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00917

EpiControl AF: 0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	RTTN: BP4, BS1, BS2 -

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2015	- -

RTTN-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.9	M;.;M
MutationTaster	Benign	0.54	D;N
PrimateAI	Benign	0.31	T
Polyphen		0.99	D;.;.
Vest4		0.37
MVP		0.51
MPC		0.17
ClinPred		0.0078	T
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

Other links and lift over

dbSNP: rs145976466; hg19: chr18-67687966; COSMIC: COSV105050690; COSMIC: COSV105050690;