18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-25_4303-11delTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_173630.4(RTTN):​c.4303-25_4303-11delTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 416,628 control chromosomes in the GnomAD database, including 6,687 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (4884 hom., cov: 0)
  • Exomes 𝑓: 0.22 (6687 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 403407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-25_4303-11delTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.4303-25_4303-11delTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 29317 AN: 68748 Hom.: 4887 Cov.: 0

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.0312 AC: 2835 AN: 90912 AF XY: 0.0283

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.0714

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0611

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.218 AC: 90682 AN: 416628 Hom.: 6687 AF XY: 0.212 AC XY: 47589 AN XY: 224578

African (AFR) AF: 0.183 AC: 1250 AN: 6828

American (AMR) AF: 0.160 AC: 2816 AN: 17584

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 2363 AN: 11614

East Asian (EAS) AF: 0.277 AC: 7280 AN: 26298

South Asian (SAS) AF: 0.137 AC: 5056 AN: 36928

European-Finnish (FIN) AF: 0.180 AC: 5322 AN: 29532

Middle Eastern (MID) AF: 0.245 AC: 363 AN: 1480

European-Non Finnish (NFE) AF: 0.230 AC: 61342 AN: 266268

Other (OTH) AF: 0.243 AC: 4890 AN: 20096

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.426 AC: 29311 AN: 68778 Hom.: 4884 Cov.: 0 AF XY: 0.430 AC XY: 13081 AN XY: 30452

African (AFR) AF: 0.297 AC: 4418 AN: 14862

American (AMR) AF: 0.503 AC: 2770 AN: 5506

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 885 AN: 2172

East Asian (EAS) AF: 0.624 AC: 1351 AN: 2164

South Asian (SAS) AF: 0.610 AC: 923 AN: 1512

European-Finnish (FIN) AF: 0.502 AC: 583 AN: 1162

Middle Eastern (MID) AF: 0.471 AC: 49 AN: 104

European-Non Finnish (NFE) AF: 0.445 AC: 17743 AN: 39842

Other (OTH) AF: 0.434 AC: 373 AN: 860

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 -

not provided Benign:1

Aug 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs531741265; hg19: chr18-67753930;