18-70127693-CTT-TTG

Variant names:

• chr18-70127693-CTT-TTG
• NM_173630.4:c.3190_3192delAAGinsCAA
• RTTN p.Lys1064Gln

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_173630.4(RTTN):​c.3190_3192delAAGinsCAA​(p.Lys1064Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_173630.4 (RTTN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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.3190_3192delAAGinsCAA	p.Lys1064Gln	missense	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.454_456delAAGinsCAA	p.Lys152Gln	missense	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.3190_3192delAAGinsCAA	p.Lys1064Gln	missense	N/A	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*1504_*1506delAAGinsCAA		non_coding_transcript_exon	Exon 24 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.*461_*463delAAGinsCAA		non_coding_transcript_exon	Exon 19 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-67794929;