rs587780444

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_173630.4(RTTN):ā€‹c.6535G>Cā€‹(p.Ala2179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,459,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000027 ( 1 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.66
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09393552).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000274 (40/1459962) while in subpopulation SAS AF= 0.000407 (35/86080). AF 95% confidence interval is 0.0003. There are 1 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RTTNNM_173630.4 linkuse as main transcriptc.6535G>C p.Ala2179Pro missense_variant 48/49 ENST00000640769.2 NP_775901.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RTTNENST00000640769.2 linkuse as main transcriptc.6535G>C p.Ala2179Pro missense_variant 48/492 NM_173630.4 ENSP00000491507 P1Q86VV8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000685
AC:
17
AN:
248290
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
134722
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000492
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000888
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1459962
Hom.:
1
Cov.:
29
AF XY:
0.0000441
AC XY:
32
AN XY:
726340
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000407
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
ExAC
AF:
0.0000745
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3472

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 26, 2022Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2179 of the RTTN protein (p.Ala2179Pro). This variant is present in population databases (rs587780444, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RTTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 130195). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 13, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.094
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.6
.;.;N
REVEL
Benign
0.23
Sift
Benign
0.058
.;.;T
Sift4G
Uncertain
0.047
.;.;D
Polyphen
0.47
P;.;.
Vest4
0.58
MutPred
0.38
Gain of glycosylation at A2179 (P = 0.0138);.;Gain of glycosylation at A2179 (P = 0.0138);
MVP
0.16
MPC
0.13
ClinPred
0.10
T
GERP RS
3.1
Varity_R
0.26
gMVP
0.54

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780444; hg19: chr18-67672494; API