rs117183725

Positions:

• chr18-70020753-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_173630.4(RTTN):​c.6015C>T​(p.Ala2005Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,613,954 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (90 hom.)
• Consequence: RTTN NM_173630.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.395

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]

RTTN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 18-70020753-G-A is Benign according to our data. Variant chr18-70020753-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70020753-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.395 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00602 (917/152284) while in subpopulation NFE AF= 0.00926 (630/68022). AF 95% confidence interval is 0.00866. There are 3 homozygotes in gnomad4. There are 448 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4	c.6015C>T	p.Ala2005Ala	synonymous_variant	45/49	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.6015C>T	p.Ala2005Ala	synonymous_variant	45/49	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00704 AC: 1753 AN: 248862 Hom.: 13 AF XY: 0.00748 AC XY: 1010 AN XY: 134976

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.00640

Gnomad NFE exome AF: 0.00900

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00936 AC: 13688 AN: 1461670 Hom.: 90 Cov.: 31 AF XY: 0.00935 AC XY: 6796 AN XY: 727152

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00689

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00931

GnomAD4 genome AF: 0.00602 AC: 917 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00602 AC XY: 448 AN XY: 74464

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00926

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00787 Hom.: 3

Bravo AF: 0.00597

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.00999

EpiControl AF: 0.00860

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RTTN: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs117183725; hg19: chr18-67687989;