chr18-70135188-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173630.4(RTTN):c.2881A>G(p.Met961Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,502,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M961I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.693

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2881A>G	p.Met961Val	missense	Exon 22 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.145A>G	p.Met49Val	missense	Exon 21 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.2881A>G	p.Met961Val	missense	Exon 22 of 49	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*1195A>G		non_coding_transcript_exon	Exon 21 of 48	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.*152A>G		non_coding_transcript_exon	Exon 16 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000845

AC:

AN:

189378

AF XY:

0.0000951

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000559

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000585

AC:

AN:

1350182

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

675182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27362

American (AMR)

AF:

0.0000379

AC:

AN:

26354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23258

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35880

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5438

European-Non Finnish (NFE)

AF:

0.0000716

AC:

AN:

1047068

Other (OTH)

AF:

0.0000179

AC:

AN:

55864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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:

0.0000788

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.0000450

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.8

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.024

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.56

M_CAP

Benign

0.0090

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.69

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.30

REVEL

Benign

0.050

Sift

Benign

0.72

Sift4G

Benign

0.91

Polyphen

0.0070

Vest4

0.098

MVP

0.24

MPC

0.071

ClinPred

0.018

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.054

gMVP

0.22

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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