rs117502718

chr18-70166070-T-C

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.1921A>G(p.Ile641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,613,612 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (90 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.878

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 (MetaRNN=0.004217416).
• BP6: Variant 18-70166070-T-C is Benign according to our data. Variant chr18-70166070-T-C is described in ClinVar as [Benign]. Clinvar id is 130168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00597 (909/152336) while in subpopulation NFE AF= 0.00924 (629/68038). AF 95% confidence interval is 0.00865. There are 3 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.1921A>G	p.Ile641Val	missense_variant	14/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.1921A>G	p.Ile641Val	missense_variant	14/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 911 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00924

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00672 AC: 1673 AN: 248946 Hom.: 12 AF XY: 0.00723 AC XY: 977 AN XY: 135068

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.00640

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.00931 AC: 13598 AN: 1461276 Hom.: 90 Cov.: 30 AF XY: 0.00930 AC XY: 6761 AN XY: 726940

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00685

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00919

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74496

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00924

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00861 Hom.: 10

Bravo AF: 0.00579

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00289 AC: 11

ESP6500EA AF: 0.00933 AC: 77

ExAC AF: 0.00675 AC: 816

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.00999

EpiControl AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RTTN: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	2.0
Dann	Benign	0.92
DEOGEN2	Benign	0.051	T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
Polyphen		0.0040	B;.;.
Vest4		0.12
MVP		0.16
MPC		0.061
ClinPred		0.0012	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.11

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: rs117502718; hg19: chr18-67833306;