18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-28_4303-11delTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_173630.4(RTTN):​c.4303-28_4303-11delTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 483,796 control chromosomes in the GnomAD database, including 32 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.027 (32 hom.)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAAAAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1190388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000499 (34/68204) while in subpopulation AFR AF = 0.00183 (27/14776). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-28_4303-11delTTTTTTTTTTTTTTTTTT		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.4303-28_4303-11delTTTTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 34 AN: 68176 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000734

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: 0.0000760

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00773 AC: 703 AN: 90912 AF XY: 0.00709

Gnomad AFR exome AF: 0.00848

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.0223

Gnomad FIN exome AF: 0.000409

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00759

GnomAD4 exome AF: 0.0274 AC: 11383 AN: 415592 Hom.: 32 AF XY: 0.0275 AC XY: 6170 AN XY: 223982

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0206 AC: 142 AN: 6880

American (AMR) AF: 0.0262 AC: 460 AN: 17586

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 275 AN: 11630

East Asian (EAS) AF: 0.0441 AC: 1149 AN: 26068

South Asian (SAS) AF: 0.0250 AC: 923 AN: 36976

European-Finnish (FIN) AF: 0.0211 AC: 622 AN: 29472

Middle Eastern (MID) AF: 0.0332 AC: 49 AN: 1474

European-Non Finnish (NFE) AF: 0.0268 AC: 7127 AN: 265474

Other (OTH) AF: 0.0317 AC: 636 AN: 20032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000499 AC: 34 AN: 68204 Hom.: 0 Cov.: 0 AF XY: 0.000563 AC XY: 17 AN XY: 30222

African (AFR) AF: 0.00183 AC: 27 AN: 14776

American (AMR) AF: 0.000733 AC: 4 AN: 5454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2146

East Asian (EAS) AF: 0.00 AC: 0 AN: 2158

South Asian (SAS) AF: 0.00 AC: 0 AN: 1510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 104

European-Non Finnish (NFE) AF: 0.0000760 AC: 3 AN: 39472

Other (OTH) AF: 0.00 AC: 0 AN: 848

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 02, 2019

GeneDx

Significance: Likely 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;