chr18-70054130-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_173630.4(RTTN):​c.5185+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

RTTN
NM_173630.4 splice_donor, intron

Scores

2
4
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.39
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022900764 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 27, new splice context is: aatGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-70054130-C-T is Pathogenic according to our data. Variant chr18-70054130-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 436607.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RTTNNM_173630.4 linkuse as main transcriptc.5185+1G>A splice_donor_variant, intron_variant ENST00000640769.2 NP_775901.3 Q86VV8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RTTNENST00000640769.2 linkuse as main transcriptc.5185+1G>A splice_donor_variant, intron_variant 2 NM_173630.4 ENSP00000491507.1 Q86VV8-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA WITH SEIZURES Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 17, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
33
DANN
Uncertain
0.98
Eigen
Pathogenic
0.81
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.86
D
GERP RS
4.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.73
Position offset: -26
DS_DL_spliceai
1.0
Position offset: 1

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.

Other links and lift over

dbSNP: rs1555707336; hg19: chr18-67721366; API