rs143471549

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.2990C>T(p.Ala997Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,612,916 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A997A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.27

Publications

1 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=0.008472055).

BP6

Variant 18-70128511-G-A is Benign according to our data. Variant chr18-70128511-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130174.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0024 (366/152204) while in subpopulation AFR AF = 0.00828 (344/41558). AF 95% confidence interval is 0.00756. There are 1 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.2990C>T	p.Ala997Val	missense	Exon 24 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.254C>T	p.Ala85Val	missense	Exon 23 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.2990C>T	p.Ala997Val	missense	Exon 24 of 49	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*1304C>T		non_coding_transcript_exon	Exon 23 of 48	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.*261C>T		non_coding_transcript_exon	Exon 18 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000984

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:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000612

AC:

152

AN:

248556

AF XY:

0.000415

show subpopulations

Gnomad AFR exome

AF:

0.00847

Gnomad AMR exome

AF:

0.000466

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.000250

AC:

365

AN:

1460712

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

171

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.00916

AC:

306

AN:

33424

American (AMR)

AF:

0.000606

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111332

Other (OTH)

AF:

0.000348

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00240

AC:

366

AN:

152204

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00828

AC:

344

AN:

41558

American (AMR)

AF:

0.000983

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

104

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:

0.000978

Hom.:

Bravo

AF:

0.00287

ESP6500AA

AF:

0.00849

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000778

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)

Inborn genetic diseases (1)

RTTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.010

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

3.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.61

Vest4

0.17

MVP

0.28

MPC

0.072

ClinPred

0.027

GERP RS

5.1

PromoterAI

0.027

Neutral

(source)

Varity_R

0.068

gMVP

0.43

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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