rs4891392

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_173630.4(RTTN):c.5282T>C (p.Phe1761Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.935 (AC=1,509,282) in the gnomAD database across 1,613,786 control chromosomes, including 717,100 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.991. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.81 ( 53926 hom., cov: 33)

Exomes 𝑓: 0.95 ( 663174 hom. )

Consequence

RTTN
NM_173630.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.01

Publications

28 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
bilateral generalized polymicrogyria
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

RTTN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_173630.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9914 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.5282T>C	p.Phe1761Ser	missense	Exon 39 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.2546T>C	p.Phe849Ser	missense	Exon 38 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.5282T>C	p.Phe1761Ser	missense	Exon 39 of 49	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*3596T>C		3_prime_UTR	Exon 38 of 48	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.*2553T>C		3_prime_UTR	Exon 33 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.807

AC:

122676

AN:

152072

Hom.:

53904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.894

Gnomad AMR

AF:

0.907

Gnomad ASJ

AF:

0.954

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.966

Gnomad FIN

AF:

0.960

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.959

Gnomad OTH

AF:

0.841

GnomAD2 exomes

AF:

0.927

AC:

231014

AN:

249198

AF XY:

0.936

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.947

Gnomad ASJ exome

AF:

0.956

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.959

Gnomad NFE exome

AF:

0.961

Gnomad OTH exome

AF:

0.939

GnomAD4 exome

AF:

0.949

AC:

1386540

AN:

1461596

Hom.:

663174

Cov.:

AF XY:

0.951

AC XY:

691320

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.403

AC:

13480

AN:

33442

American (AMR)

AF:

0.942

AC:

42092

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.955

AC:

24969

AN:

26132

East Asian (EAS)

AF:

1.00

AC:

39676

AN:

39690

South Asian (SAS)

AF:

0.963

AC:

83023

AN:

86242

European-Finnish (FIN)

AF:

0.960

AC:

51297

AN:

53416

Middle Eastern (MID)

AF:

0.893

AC:

5149

AN:

5766

European-Non Finnish (NFE)

AF:

0.963

AC:

1070909

AN:

1111850

Other (OTH)

AF:

0.927

AC:

55945

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2955

5910

8866

11821

14776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21542

43084

64626

86168

107710

<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:

0.807

AC:

122742

AN:

152190

Hom.:

53926

Cov.:

AF XY:

0.812

AC XY:

60422

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.420

AC:

17425

AN:

41450

American (AMR)

AF:

0.907

AC:

13885

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.954

AC:

3311

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5175

AN:

5178

South Asian (SAS)

AF:

0.967

AC:

4665

AN:

4826

European-Finnish (FIN)

AF:

0.960

AC:

10184

AN:

10612

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.959

AC:

65253

AN:

68032

Other (OTH)

AF:

0.843

AC:

1780

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

784

1567

2351

3134

3918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.910

Hom.:

218532

Bravo

AF:

0.783

Asia WGS

AF:

0.941

AC:

3271

AN:

3478

EpiCase

AF:

0.959

EpiControl

AF:

0.960

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

1.00

AC:

122838

AN:

122844

Turkish Variome

AF:

0.950

AC:

6314

AN:

6644

Hom.:

3001

WBBC (Westlake BioBank for Chinese) pilot

AF:

1.00

AC:

8958

AN:

8960

Hom.:

4478

ABraOM SABE-WGS-1171

AF:

0.837

AC:

1961

AN:

2342

Hom.:

838

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Microcephalic primordial dwarfism due to RTTN deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.025

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.036

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.18

MetaRNN

Benign

7.3e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

PhyloP100

-1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

2.2

REVEL

Benign

0.018

Sift

Benign

0.98

Sift4G

Benign

0.67

Varity_R

0.048

gMVP

0.15

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over