rs113536228

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_173630.4(RTTN):c.2536G>A(p.Val846Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,609,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00080 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000082 ( 1 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.405

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066359043).

BP6

Variant 18-70142333-C-T is Benign according to our data. Variant chr18-70142333-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436609.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000799 (121/151402) while in subpopulation AFR AF = 0.00252 (104/41194). AF 95% confidence interval is 0.00213. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.2536G>A	p.Val846Ile	missense	Exon 19 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.-112G>A		5_prime_UTR	Exon 19 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.2536G>A	p.Val846Ile	missense	Exon 19 of 49	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*939G>A		non_coding_transcript_exon	Exon 19 of 48	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.1906G>A		non_coding_transcript_exon	Exon 14 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.000773

AC:

117

AN:

151292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000182

AC:

AN:

247260

AF XY:

0.000179

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000823

AC:

120

AN:

1457672

Hom.:

Cov.:

AF XY:

0.0000772

AC XY:

AN XY:

725422

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33432

American (AMR)

AF:

0.000246

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110536

Other (OTH)

AF:

0.000497

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000799

AC:

121

AN:

151402

Hom.:

Cov.:

AF XY:

0.000825

AC XY:

AN XY:

73904

show subpopulations

African (AFR)

AF:

0.00252

AC:

104

AN:

41194

American (AMR)

AF:

0.000659

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67934

Other (OTH)

AF:

0.00190

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000313

Hom.:

Bravo

AF:

0.000926

ESP6500AA

AF:

0.00348

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000232

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

RTTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.14

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.70

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

0.41

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.63

REVEL

Benign

0.058

Sift

Benign

0.38

Sift4G

Benign

0.34

Polyphen

0.76

Vest4

0.092

MVP

0.061

MPC

0.14

ClinPred

0.016

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.089

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over