chr18-70086694-TAAAAAAAAAAAAAAAAAA-T

Position:

• chr18-70086694-TAAAAAAAAAAAAAAAAAA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_173630.4(RTTN):​c.4303-28_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 0.0236 in 483,796 control chromosomes in the GnomAD database, including 32 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.027 (32 hom.)
• 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 Benign. Variant got -10 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAAAAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1190388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000499 (34/68204) while in subpopulation AFR AF= 0.00183 (27/14776). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-28_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.4303-28_4303-11del		splice_polypyrimidine_tract_variant, intron_variant		2	NM_173630.4	ENSP00000491507	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 34 AN: 68176 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000734

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: 0.0000760

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00773 AC: 703 AN: 90912 Hom.: 0 AF XY: 0.00709 AC XY: 369 AN XY: 52036

Gnomad AFR exome AF: 0.00848

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.0223

Gnomad SAS exome AF: 0.00881

Gnomad FIN exome AF: 0.000409

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00759

GnomAD4 exome AF: 0.0274 AC: 11383 AN: 415592 Hom.: 32 AF XY: 0.0275 AC XY: 6170 AN XY: 223982

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.0262

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.0441

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.000499 AC: 34 AN: 68204 Hom.: 0 Cov.: 0 AF XY: 0.000563 AC XY: 17 AN XY: 30222

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000733

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000760

Gnomad4 OTH AF: 0.00

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

Oct 02, 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;