18-70051452-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01

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=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	UniProt
RTTN	NM_173630.4	c.5282T>C	p.Phe1761Ser	missense_variant	39/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.5282T>C	p.Phe1761Ser	missense_variant	39/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122676 AN: 152072 Hom.: 53904 Cov.: 33

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

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.: 45 AF XY: 0.951 AC XY: 691320 AN XY: 727110

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.: 33 AF XY: 0.812 AC XY: 60422 AN XY: 74406

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 -
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. -

Microcephalic primordial dwarfism due to RTTN deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.86	T
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	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	7.3e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
Polyphen		0.0	B;.
Vest4		0.012
MPC		0.12
ClinPred		0.0067	T
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

Other links and lift over

dbSNP: rs4891392; hg19: chr18-67718688;