18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-24_4303-11delTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_173630.4(RTTN):​c.4303-24_4303-11delTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.067 in 415,484 control chromosomes in the GnomAD database, including 1,188 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 0.20 (1074 hom., cov: 0)
  • Exomes 𝑓: 0.067 (1188 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign/Likely 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 -12 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1295486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 1188 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-24_4303-11delTTTTTTTTTTTTTT		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.4303-24_4303-11delTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 13745 AN: 68692 Hom.: 1075 Cov.: 0

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.208

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.00833 AC: 757 AN: 90912 AF XY: 0.00744

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.00849

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00663

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0670 AC: 27822 AN: 415484 Hom.: 1188 AF XY: 0.0653 AC XY: 14630 AN XY: 223948

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

African (AFR) AF: 0.0829 AC: 568 AN: 6852

American (AMR) AF: 0.0524 AC: 921 AN: 17576

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 1022 AN: 11576

East Asian (EAS) AF: 0.0486 AC: 1274 AN: 26196

South Asian (SAS) AF: 0.0272 AC: 1006 AN: 36928

European-Finnish (FIN) AF: 0.0686 AC: 2018 AN: 29438

Middle Eastern (MID) AF: 0.0856 AC: 126 AN: 1472

European-Non Finnish (NFE) AF: 0.0728 AC: 19326 AN: 265470

Other (OTH) AF: 0.0781 AC: 1561 AN: 19976

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.200 AC: 13741 AN: 68720 Hom.: 1074 Cov.: 0 AF XY: 0.195 AC XY: 5944 AN XY: 30422

African (AFR) AF: 0.171 AC: 2534 AN: 14826

American (AMR) AF: 0.221 AC: 1215 AN: 5498

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 604 AN: 2170

East Asian (EAS) AF: 0.0494 AC: 107 AN: 2166

South Asian (SAS) AF: 0.120 AC: 183 AN: 1524

European-Finnish (FIN) AF: 0.215 AC: 249 AN: 1156

Middle Eastern (MID) AF: 0.206 AC: 21 AN: 102

European-Non Finnish (NFE) AF: 0.213 AC: 8479 AN: 39836

Other (OTH) AF: 0.213 AC: 182 AN: 856

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 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;