rs199597732

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_173630.4(RTTN):c.4303-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

RTTN
NM_173630.4 splice_region, intron

Scores

Splicing: ADA: 0.00002205

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.734

Publications

0 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 (BayesDel_noAF=-0.82).

BP6

Variant 18-70086692-T-C is Benign according to our data. Variant chr18-70086692-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130180.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (35/18004) while in subpopulation AFR AF = 0.00838 (32/3818). AF 95% confidence interval is 0.0061. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.4303-8A>G		splice_region intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-8A>G		splice_region intron	N/A	NP_001305449.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RTTN	ENST00000640769.2	TSL:2 MANE Select	c.4303-8A>G	splice_region intron	N/A	ENSP00000491507.1	Q86VV8-1
RTTN	ENST00000581161.5	TSL:1	n.*2617-8A>G	splice_region intron	N/A	ENSP00000462926.1	J3KTD2
RTTN	ENST00000583043.5	TSL:1	n.*1574-8A>G	splice_region intron	N/A	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

AN:

18004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00838

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00182

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:

0.0000950

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000178

AC:

AN:

89732

AF XY:

0.000153

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.000139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000720

AC:

AN:

152706

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

84258

show subpopulations

African (AFR)

AF:

0.00456

AC:

AN:

2412

American (AMR)

AF:

0.00

AC:

AN:

8548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4968

East Asian (EAS)

AF:

0.00

AC:

AN:

9170

South Asian (SAS)

AF:

0.00

AC:

AN:

14542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

462

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

89768

Other (OTH)

AF:

0.00

AC:

AN:

6370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00194

AC:

AN:

18004

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

AN XY:

7948

show subpopulations

African (AFR)

AF:

0.00838

AC:

AN:

3818

American (AMR)

AF:

0.00182

AC:

AN:

1096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

512

East Asian (EAS)

AF:

0.00

AC:

AN:

662

South Asian (SAS)

AF:

0.00

AC:

AN:

592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000950

AC:

AN:

10530

Other (OTH)

AF:

0.00

AC:

AN:

214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.0

(source)

DANN

Benign

0.69

PhyloP100

-0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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

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