rs34989098

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173630.4(RTTN):c.6445G>A(p.Ala2149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,800 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 63 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.376

Publications

11 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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00667727).

BP6

Variant 18-70006461-C-T is Benign according to our data. Variant chr18-70006461-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130194.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00609 (927/152336) while in subpopulation AMR AF = 0.00921 (141/15304). AF 95% confidence interval is 0.00846. There are 5 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.6445G>A	p.Ala2149Thr	missense	Exon 47 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.3709G>A	p.Ala1237Thr	missense	Exon 46 of 48	NP_001305449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTTN	ENST00000640769.2	TSL:2 MANE Select	c.6445G>A	p.Ala2149Thr	missense	Exon 47 of 49	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*4759G>A		non_coding_transcript_exon	Exon 46 of 48	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.*3685G>A		non_coding_transcript_exon	Exon 41 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.00608

AC:

926

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00904

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00577

AC:

1438

AN:

249042

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.000840

Gnomad AMR exome

AF:

0.00417

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00941

Gnomad NFE exome

AF:

0.00853

Gnomad OTH exome

AF:

0.00579

GnomAD4 exome

AF:

0.00621

AC:

9077

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

4587

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33478

American (AMR)

AF:

0.00472

AC:

211

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

114

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.00114

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00968

AC:

517

AN:

53410

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00699

AC:

7765

AN:

1111660

Other (OTH)

AF:

0.00533

AC:

322

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

450

900

1351

1801

2251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00609

AC:

927

AN:

152336

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

439

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41578

American (AMR)

AF:

0.00921

AC:

141

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00838

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00905

AC:

616

AN:

68030

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

124

166

207

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:

0.00736

Hom.:

Bravo

AF:

0.00557

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000815

AC:

ESP6500EA

AF:

0.00808

AC:

ExAC

AF:

0.00571

AC:

690

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00611

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

Microcephalic primordial dwarfism due to RTTN deficiency (1)

not specified (1)

RTTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.9

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.022

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.69

M_CAP

Benign

0.0066

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

-0.38

PrimateAI

Benign

0.27

PROVEAN

Benign

0.050

REVEL

Benign

0.059

Sift

Benign

0.64

Sift4G

Benign

0.89

Polyphen

0.0010

Vest4

0.095

MVP

0.095

MPC

0.068

ClinPred

0.0043

GERP RS

1.1

Varity_R

0.034

gMVP

0.043

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over