18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Position:

• chr18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_173630.4(RTTN):​c.4303-24_4303-11delTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.067 in 415,484 control chromosomes in the GnomAD database, including 1,188 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (1074 hom., cov: 0)
  • Exomes 𝑓: 0.067 (1188 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1295486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-24_4303-11delTTTTTTTTTTTTTT		intron_variant		ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.4303-24_4303-11delTTTTTTTTTTTTTT		intron_variant		2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13745 AN: 68692 Hom.: 1075 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.208

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.00833 AC: 757 AN: 90912 Hom.: 3 AF XY: 0.00744 AC XY: 387 AN XY: 52036

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.00849

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00663

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0670 AC: 27822 AN: 415484 Hom.: 1188 AF XY: 0.0653 AC XY: 14630 AN XY: 223948

Gnomad4 AFR exome AF: 0.0829

Gnomad4 AMR exome AF: 0.0524

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.0486

Gnomad4 SAS exome AF: 0.0272

Gnomad4 FIN exome AF: 0.0686

Gnomad4 NFE exome AF: 0.0728

Gnomad4 OTH exome AF: 0.0781

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.200 AC: 13741 AN: 68720 Hom.: 1074 Cov.: 0 AF XY: 0.195 AC XY: 5944 AN XY: 30422

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 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;