rs201884120
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_173630.4(RTTN):c.80G>A(p.Cys27Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
RTTN
NM_173630.4 missense
NM_173630.4 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 1.64
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19967976).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249564Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135394
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727246
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GnomAD4 genome AF: 0.0000919 AC: 14AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2017 | A variant of uncertain significance has been identified in the RTTN gene. The C27Y variant has been previously reported in the homozygous state in an individual with bilateral polymicrogyria, seizures, spasticity, and severe intellectual disability. Parental carrier testing confirmed inheritance; however, functional characterization of the variant was not completed (Kheradmand et al., 2012). The C27Y variant is observed in 4/9798 (0.04%) alleles from individuals of Afican background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C27Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA WITH SEIZURES Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 07, 2012 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 15, 2024 | The c.80G>A (p.C27Y) alteration is located in exon 2 (coding exon 2) of the RTTN gene. This alteration results from a G to A substitution at nucleotide position 80, causing the cysteine (C) at amino acid position 27 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Benign
.;T
Sift4G
Benign
.;T
Polyphen
D;.
Vest4
0.54
MVP
0.39
MPC
0.22
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at