rs117843366

Positions:

• chr18-70150601-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173630.4(RTTN):​c.2055+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,610,260 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 33)
  • Exomes 𝑓: 0.021 (411 hom.)
• Consequence: RTTN NM_173630.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001870
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.400

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-70150601-G-A is Benign according to our data. Variant chr18-70150601-G-A is described in ClinVar as [Benign]. Clinvar id is 130169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70150601-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2513/152186) while in subpopulation NFE AF= 0.0252 (1711/68004). AF 95% confidence interval is 0.0242. There are 40 homozygotes in gnomad4. There are 1198 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.2055+7C>T		splice_region_variant, intron_variant		ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.2055+7C>T		splice_region_variant, intron_variant		2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2511 AN: 152068 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0158 AC: 3941 AN: 248682 Hom.: 59 AF XY: 0.0155 AC XY: 2094 AN XY: 134920

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0215 AC: 31279 AN: 1458074 Hom.: 411 Cov.: 29 AF XY: 0.0208 AC XY: 15090 AN XY: 725574

Gnomad4 AFR exome AF: 0.00431

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0255

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0165 AC: 2513 AN: 152186 Hom.: 40 Cov.: 33 AF XY: 0.0161 AC XY: 1198 AN XY: 74408

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0204 Hom.: 17

Bravo AF: 0.0170

Asia WGS AF: 0.00202 AC: 7 AN: 3472

EpiCase AF: 0.0251

EpiControl AF: 0.0271

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, outside splice consensus -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs117843366; hg19: chr18-67817837;