18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-32_4303-11delTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_173630.4(RTTN):​c.4303-32_4303-11delTTTTTTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000841 in 487,714 control chromosomes in the GnomAD database, including 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00010 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000081 (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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000103 (7/68178) while in subpopulation AFR AF = 0.000475 (7/14748). AF 95% confidence interval is 0.000223. There are 1 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-32_4303-11delTTTTTTTTTTTTTTTTTTTTTT		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.4303-32_4303-11delTTTTTTTTTTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 7 AN: 68178 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000475

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: 0.0000810 AC: 34 AN: 419536 Hom.: 0 AF XY: 0.0000884 AC XY: 20 AN XY: 226154

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

African (AFR) AF: 0.000722 AC: 5 AN: 6928

American (AMR) AF: 0.0000564 AC: 1 AN: 17746

Ashkenazi Jewish (ASJ) AF: 0.000342 AC: 4 AN: 11712

East Asian (EAS) AF: 0.000113 AC: 3 AN: 26520

South Asian (SAS) AF: 0.0000807 AC: 3 AN: 37166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1492

European-Non Finnish (NFE) AF: 0.0000634 AC: 17 AN: 268056

Other (OTH) AF: 0.0000494 AC: 1 AN: 20242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000295319), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000103 AC: 7 AN: 68178 Hom.: 1 Cov.: 0 AF XY: 0.0000662 AC XY: 2 AN XY: 30196

African (AFR) AF: 0.000475 AC: 7 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 v4.3

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;