18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-31_4303-11delTTTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_173630.4(RTTN):​c.4303-31_4303-11delTTTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 419,348 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 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00029 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.4303-31_4303-11delTTTTTTTTTTTTTTTTTTTTT		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-31_1567-11delTTTTTTTTTTTTTTTTTTTTT		intron	N/A	NP_001305449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.4303-31_4303-11delTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2617-31_*2617-11delTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1574-31_*1574-11delTTTTTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 68178 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000293 AC: 123 AN: 419348 Hom.: 0 AF XY: 0.000327 AC XY: 74 AN XY: 226058

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

African (AFR) AF: 0.000289 AC: 2 AN: 6928

American (AMR) AF: 0.000338 AC: 6 AN: 17744

Ashkenazi Jewish (ASJ) AF: 0.000513 AC: 6 AN: 11690

East Asian (EAS) AF: 0.000302 AC: 8 AN: 26508

South Asian (SAS) AF: 0.000350 AC: 13 AN: 37154

European-Finnish (FIN) AF: 0.000236 AC: 7 AN: 29668

Middle Eastern (MID) AF: 0.000671 AC: 1 AN: 1490

European-Non Finnish (NFE) AF: 0.000280 AC: 75 AN: 267936

Other (OTH) AF: 0.000247 AC: 5 AN: 20230

⚠️ 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: AC0 AF: 0.00 AC: 0 AN: 68178 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30196

African (AFR) AF: 0.00 AC: 0 AN: 14748

American (AMR) AF: 0.00 AC: 0 AN: 5454

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2162

South Asian (SAS) AF: 0.00 AC: 0 AN: 1518

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39470

Other (OTH) AF: 0.00 AC: 0 AN: 836

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=97/3	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;