18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-29_4303-11delTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173630.4(RTTN):​c.4303-29_4303-11delTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 485,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000088 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0069 (0 hom.)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the MID (0.00988) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-29_4303-11delTTTTTTTTTTTTTTTTTTT		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.4303-29_4303-11delTTTTTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.0000880 AC: 6 AN: 68176 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000868

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000253

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00225 AC: 205 AN: 90912 AF XY: 0.00213

Gnomad AFR exome AF: 0.00321

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.000729

Gnomad EAS exome AF: 0.00561

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00690 AC: 2883 AN: 417586 Hom.: 0 AF XY: 0.00709 AC XY: 1596 AN XY: 225116

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

African (AFR) AF: 0.00493 AC: 34 AN: 6898

American (AMR) AF: 0.00713 AC: 126 AN: 17664

Ashkenazi Jewish (ASJ) AF: 0.00703 AC: 82 AN: 11664

East Asian (EAS) AF: 0.0109 AC: 287 AN: 26282

South Asian (SAS) AF: 0.00618 AC: 229 AN: 37040

European-Finnish (FIN) AF: 0.00569 AC: 168 AN: 29528

Middle Eastern (MID) AF: 0.0114 AC: 17 AN: 1488

European-Non Finnish (NFE) AF: 0.00660 AC: 1761 AN: 266850

Other (OTH) AF: 0.00887 AC: 179 AN: 20172

⚠️ 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: 0.0000880 AC: 6 AN: 68204 Hom.: 0 Cov.: 0 AF XY: 0.0000662 AC XY: 2 AN XY: 30224

African (AFR) AF: 0.000271 AC: 4 AN: 14776

American (AMR) AF: 0.00 AC: 0 AN: 5456

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: 0.000868 AC: 1 AN: 1152

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

European-Non Finnish (NFE) AF: 0.0000253 AC: 1 AN: 39470

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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;