18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-26_4303-11delTTTTTTTTTTTTTTTT

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.4303-26_4303-11delTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 415,838 control chromosomes in the GnomAD database, including 3,224 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 0.013 (13 hom., cov: 0)
  • Exomes 𝑓: 0.18 (3224 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-TAAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 403408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-26_4303-11delTTTTTTTTTTTTTTTT		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.4303-26_4303-11delTTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 878 AN: 68214 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.000932

Gnomad EAS AF: 0.0301

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.00174

Gnomad MID AF: 0.00926

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.0391 AC: 3558 AN: 90912 AF XY: 0.0351

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.0842

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.0961

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0617

GnomAD4 exome AF: 0.178 AC: 74030 AN: 415838 Hom.: 3224 AF XY: 0.176 AC XY: 39364 AN XY: 224122

African (AFR) AF: 0.156 AC: 1063 AN: 6802

American (AMR) AF: 0.153 AC: 2681 AN: 17564

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 1916 AN: 11582

East Asian (EAS) AF: 0.241 AC: 6334 AN: 26286

South Asian (SAS) AF: 0.141 AC: 5176 AN: 36814

European-Finnish (FIN) AF: 0.145 AC: 4272 AN: 29488

Middle Eastern (MID) AF: 0.203 AC: 302 AN: 1488

European-Non Finnish (NFE) AF: 0.182 AC: 48276 AN: 265750

Other (OTH) AF: 0.200 AC: 4010 AN: 20064

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0129 AC: 881 AN: 68242 Hom.: 13 Cov.: 0 AF XY: 0.0131 AC XY: 396 AN XY: 30244

African (AFR) AF: 0.0206 AC: 305 AN: 14792

American (AMR) AF: 0.0147 AC: 80 AN: 5460

Ashkenazi Jewish (ASJ) AF: 0.000932 AC: 2 AN: 2146

East Asian (EAS) AF: 0.0301 AC: 65 AN: 2158

South Asian (SAS) AF: 0.0252 AC: 38 AN: 1510

European-Finnish (FIN) AF: 0.00174 AC: 2 AN: 1152

Middle Eastern (MID) AF: 0.00962 AC: 1 AN: 104

European-Non Finnish (NFE) AF: 0.00952 AC: 376 AN: 39488

Other (OTH) AF: 0.0142 AC: 12 AN: 848

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 18, 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

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;