NM_173630.4:c.725_727dupGAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBA1

The NM_173630.4(RTTN):c.725_727dupGAG(p.Gly242dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,613,158 control chromosomes in the GnomAD database, including 794,838 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70117 hom., cov: 0)

Exomes 𝑓: 1.0 ( 724721 hom. )

Consequence

RTTN
NM_173630.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.14

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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 -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_173630.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 18-70196614-T-TCTC is Benign according to our data. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70196614-T-TCTC is described in CliVar as Benign. Clinvar id is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4 link	c.725_727dupGAG	p.Gly242dup	conservative_inframe_insertion	Exon 7 of 49	ENST00000640769.2	NP_775901.3	Q86VV8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2 link	c.725_727dupGAG	p.Gly242dup	conservative_inframe_insertion	Exon 7 of 49	2	NM_173630.4	ENSP00000491507.1		Q86VV8-1

Frequencies

GnomAD3 genomes

AF:

0.958

AC:

145560

AN:

151880

Hom.:

70067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.855

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.986

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.974

GnomAD2 exomes

AF:

0.989

AC:

246318

AN:

248976

AF XY:

0.992

show subpopulations

Gnomad AFR exome

AF:

0.849

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.996

GnomAD4 exome

AF:

0.996

AC:

1454914

AN:

1461160

Hom.:

724721

Cov.:

AF XY:

0.996

AC XY:

724212

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.854

AC:

28521

AN:

33384

American (AMR)

AF:

0.992

AC:

44308

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26126

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39671

AN:

39672

South Asian (SAS)

AF:

1.00

AC:

86145

AN:

86170

European-Finnish (FIN)

AF:

1.00

AC:

53413

AN:

53414

Middle Eastern (MID)

AF:

0.993

AC:

5721

AN:

5764

European-Non Finnish (NFE)

AF:

1.00

AC:

1111207

AN:

1111624

Other (OTH)

AF:

0.991

AC:

59802

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

250

499

749

998

1248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21660

43320

64980

86640

108300

<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:

0.958

AC:

145669

AN:

151998

Hom.:

70117

Cov.:

AF XY:

0.960

AC XY:

71296

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.855

AC:

35360

AN:

41370

American (AMR)

AF:

0.986

AC:

15065

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3464

AN:

3464

East Asian (EAS)

AF:

1.00

AC:

5166

AN:

5166

South Asian (SAS)

AF:

0.999

AC:

4809

AN:

4812

European-Finnish (FIN)

AF:

1.00

AC:

10588

AN:

10588

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67959

AN:

68002

Other (OTH)

AF:

0.974

AC:

2058

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

272

544

817

1089

1361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.977

Hom.:

12154

Asia WGS

AF:

0.991

AC:

3446

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Disease Association NOS

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic primordial dwarfism due to RTTN deficiency

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over