rs62089120

chr18-70088098-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_173630.4(RTTN):c.4193C>T(p.Thr1398Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,613,870 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (16 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.248

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068203807).
• BP6: Variant 18-70088098-G-A is Benign according to our data. Variant chr18-70088098-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436608.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr18-70088098-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (318/152288) while in subpopulation NFE AF= 0.00412 (280/68014). AF 95% confidence interval is 0.00372. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.4193C>T	p.Thr1398Met	missense_variant	31/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.4193C>T	p.Thr1398Met	missense_variant	31/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00183 AC: 455 AN: 249216 Hom.: 0 AF XY: 0.00182 AC XY: 246 AN XY: 135216

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00355 AC: 5191 AN: 1461582 Hom.: 16 Cov.: 31 AF XY: 0.00346 AC XY: 2519 AN XY: 727096

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74460

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00204

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00131 AC: 5

ESP6500EA AF: 0.00523 AC: 43

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00426

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RTTN: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2023	See Variant Classification Assertion Criteria. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2015

- -

RTTN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
Polyphen		0.93	P;.
Vest4		0.24
MVP		0.44
MPC		0.10
ClinPred		0.016	T
GERP RS		3.4
Varity_R		0.022
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62089120; hg19: chr18-67755334;