rs34989098

chr18-70006461-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173630.4(RTTN):c.6445G>A(p.Ala2149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,800 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (63 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.376

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00667727).
• BP6: Variant 18-70006461-C-T is Benign according to our data. Variant chr18-70006461-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130194.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00609 (927/152336) while in subpopulation AMR AF= 0.00921 (141/15304). AF 95% confidence interval is 0.00846. There are 5 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.6445G>A	p.Ala2149Thr	missense_variant	47/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.6445G>A	p.Ala2149Thr	missense_variant	47/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152218 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00577 AC: 1438 AN: 249042 Hom.: 9 AF XY: 0.00604 AC XY: 816 AN XY: 135086

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00941

Gnomad NFE exome AF: 0.00853

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00621 AC: 9077 AN: 1461464 Hom.: 63 Cov.: 29 AF XY: 0.00631 AC XY: 4587 AN XY: 727056

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00968

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00609 AC: 927 AN: 152336 Hom.: 5 Cov.: 32 AF XY: 0.00589 AC XY: 439 AN XY: 74506

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.00905

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00743 Hom.: 8

Bravo AF: 0.00557

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000815 AC: 3

ESP6500EA AF: 0.00808 AC: 66

ExAC AF: 0.00571 AC: 690

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RTTN: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	- -

Microcephalic primordial dwarfism due to RTTN deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

Possible pathogenicity based on finding it once in our laboratory in trans with another missense variant in a 3-year-old female with microcephaly, craniosynostosis, dysmorphisms, fused labia, absence seizures, failure to thrive. However, allele frequency is high, and homozygotes have been found in controls. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 05, 2015

- -

RTTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2022

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	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.9
Dann	Benign	0.87
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.27	T
Polyphen		0.0010	B;.;.
Vest4		0.095
MVP		0.095
MPC		0.068
ClinPred		0.0043	T
GERP RS		1.1
Varity_R		0.034
gMVP		0.043

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: rs34989098; hg19: chr18-67673697;