rs117502718

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173630.4(RTTN):c.1921A>G(p.Ile641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,613,612 control chromosomes in the GnomAD database, including 93 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 90 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.878

Publications

8 publications found

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]

RTTN Gene-Disease associations (from GenCC):

microcephalic primordial dwarfism due to RTTN deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
bilateral generalized polymicrogyria
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

RTTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004217416).

BP6

Variant 18-70166070-T-C is Benign according to our data. Variant chr18-70166070-T-C is described in ClinVar as Benign. ClinVar VariationId is 130168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00597 (909/152336) while in subpopulation NFE AF = 0.00924 (629/68038). AF 95% confidence interval is 0.00865. There are 3 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4 link	c.1921A>G	p.Ile641Val	missense_variant	Exon 14 of 49	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2 link	c.1921A>G	p.Ile641Val	missense_variant	Exon 14 of 49	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes

AF:

0.00598

AC:

911

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00924

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00672

AC:

1673

AN:

248946

AF XY:

0.00723

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00587

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00640

Gnomad NFE exome

AF:

0.00898

Gnomad OTH exome

AF:

0.00696

GnomAD4 exome

AF:

0.00931

AC:

13598

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

6761

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33466

American (AMR)

AF:

0.00239

AC:

107

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00597

AC:

156

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.0100

AC:

863

AN:

86180

European-Finnish (FIN)

AF:

0.00685

AC:

366

AN:

53396

Middle Eastern (MID)

AF:

0.0236

AC:

136

AN:

5764

European-Non Finnish (NFE)

AF:

0.0102

AC:

11345

AN:

1111648

Other (OTH)

AF:

0.00919

AC:

555

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

587

1174

1761

2348

2935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

452

904

1356

1808

2260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00597

AC:

909

AN:

152336

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

445

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41578

American (AMR)

AF:

0.00386

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00808

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00924

AC:

629

AN:

68038

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00825

Hom.:

Bravo

AF:

0.00579

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00289

AC:

ESP6500EA

AF:

0.00933

AC:

ExAC

AF:

0.00675

AC:

816

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00999

EpiControl

AF:

0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTTN: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 07, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

RTTN-related disorder

Benign:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.087

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.0

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

0.88

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

.;N;.

REVEL

Benign

0.018

Sift

Benign

0.26

.;T;.

Sift4G

Benign

0.35

.;T;.

Polyphen

0.0040

B;.;.

Vest4

0.12

MVP

0.16

MPC

0.061

ClinPred

0.0012

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.11

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over