18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

Position:

• chr18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_173630.4(RTTN):​c.4303-22_4303-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 419,226 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (26 hom., cov: 0)
  • Exomes 𝑓: 0.00098 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAA-T is described in ClinVar as [Benign]. Clinvar id is 1271007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000978 (410/419226) while in subpopulation AFR AF= 0.0131 (90/6894). AF 95% confidence interval is 0.0109. There are 1 homozygotes in gnomad4_exome. There are 194 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-22_4303-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.4303-22_4303-11del		splice_polypyrimidine_tract_variant, intron_variant		2	NM_173630.4	ENSP00000491507	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1228 AN: 68144 Hom.: 26 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00862

Gnomad ASJ AF: 0.00140

Gnomad EAS AF: 0.000463

Gnomad SAS AF: 0.000659

Gnomad FIN AF: 0.00260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.000978 AC: 410 AN: 419226 Hom.: 1 AF XY: 0.000859 AC XY: 194 AN XY: 225974

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.000790

Gnomad4 ASJ exome AF: 0.000940

Gnomad4 EAS exome AF: 0.000452

Gnomad4 SAS exome AF: 0.000377

Gnomad4 FIN exome AF: 0.000809

Gnomad4 NFE exome AF: 0.000769

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0180 AC: 1230 AN: 68172 Hom.: 26 Cov.: 0 AF XY: 0.0183 AC XY: 554 AN XY: 30204

Gnomad4 AFR AF: 0.0695

Gnomad4 AMR AF: 0.00861

Gnomad4 ASJ AF: 0.00140

Gnomad4 EAS AF: 0.000463

Gnomad4 SAS AF: 0.000662

Gnomad4 FIN AF: 0.00260

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.0118

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs531741265; hg19: chr18-67753930;