chr18-70086694-TAAAAAAAAAAA-T

Position:

• chr18-70086694-TAAAAAAAAAAA-T

Variant summary

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

The NM_173630.4(RTTN):​c.4303-21_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 0.000198 in 419,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely 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-TAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206963.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 = 0.000198 (83/419556) while in subpopulation AFR AF= 0.00159 (11/6918). AF 95% confidence interval is 0.000891. There are 0 homozygotes in gnomad4_exome. There are 52 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.4303-21_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.4303-21_4303-11del		splice_polypyrimidine_tract_variant, intron_variant		2	NM_173630.4	ENSP00000491507	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 194 AN: 68168 Hom.: 2 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00926

Gnomad NFE AF: 0.000203

Gnomad OTH AF: 0.00359

GnomAD4 exome AF: 0.000198 AC: 83 AN: 419556 Hom.: 0 AF XY: 0.000230 AC XY: 52 AN XY: 226172

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.0000854

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000807

Gnomad4 FIN exome AF: 0.000270

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.000395

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00284 AC: 194 AN: 68196 Hom.: 2 Cov.: 0 AF XY: 0.00252 AC XY: 76 AN XY: 30218

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000203

Gnomad4 OTH AF: 0.00354

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 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;