18-70204107-A-C

Variant names:

• chr18-70204107-A-C
• rs3911730
• NM_173630.4:c.376T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173630.4(RTTN):​c.376T>G​(p.Ser126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,611,712 control chromosomes in the GnomAD database, including 657,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (47512 hom., cov: 31)
  • Exomes 𝑓: 0.91 (610305 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.16
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism due to RTTN deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8645148E-6).
• BP6: Variant 18-70204107-A-C is Benign according to our data. Variant chr18-70204107-A-C is described in ClinVar as Benign. ClinVar VariationId is 130179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.376T>G	p.Ser126Ala	missense	Exon 3 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.-2178T>G		5_prime_UTR	Exon 3 of 48	NP_001305449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.376T>G	p.Ser126Ala	missense	Exon 3 of 49	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.376T>G		non_coding_transcript_exon	Exon 3 of 48	ENSP00000462926.1
	RTTN	ENST00000255674.11	TSL:5	c.376T>G	p.Ser126Ala	missense	Exon 3 of 49	ENSP00000255674.7

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111245 AN: 152040 Hom.: 47507 Cov.: 31

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.907

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.875 AC: 217592 AN: 248674 AF XY: 0.887

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.875

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.910

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.892

GnomAD4 exome AF: 0.908 AC: 1325118 AN: 1459554 Hom.: 610305 Cov.: 34 AF XY: 0.910 AC XY: 660661 AN XY: 726178

African (AFR) AF: 0.232 AC: 7744 AN: 33362

American (AMR) AF: 0.868 AC: 38690 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 23806 AN: 26090

East Asian (EAS) AF: 0.999 AC: 39631 AN: 39670

South Asian (SAS) AF: 0.906 AC: 77906 AN: 86008

European-Finnish (FIN) AF: 0.911 AC: 48655 AN: 53404

Middle Eastern (MID) AF: 0.853 AC: 4913 AN: 5762

European-Non Finnish (NFE) AF: 0.928 AC: 1030766 AN: 1110404

Other (OTH) AF: 0.879 AC: 53007 AN: 60302

GnomAD4 genome AF: 0.731 AC: 111278 AN: 152158 Hom.: 47512 Cov.: 31 AF XY: 0.737 AC XY: 54863 AN XY: 74400

African (AFR) AF: 0.253 AC: 10491 AN: 41454

American (AMR) AF: 0.846 AC: 12942 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3183 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5168 AN: 5186

South Asian (SAS) AF: 0.907 AC: 4380 AN: 4828

European-Finnish (FIN) AF: 0.910 AC: 9646 AN: 10600

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.922 AC: 62716 AN: 68012

Other (OTH) AF: 0.774 AC: 1635 AN: 2112

Alfa AF: 0.861 Hom.: 251226

Bravo AF: 0.703

TwinsUK AF: 0.928 AC: 3442

ALSPAC AF: 0.931 AC: 3590

ESP6500AA AF: 0.291 AC: 1071

ESP6500EA AF: 0.924 AC: 7553

ExAC AF: 0.865 AC: 104503

Asia WGS AF: 0.897 AC: 3116 AN: 3478

EpiCase AF: 0.923

EpiControl AF: 0.924

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 21, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcephalic primordial dwarfism due to RTTN deficiency Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.15
DANN	Benign	0.78
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.061
Sift	Benign	0.70	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.064
ClinPred		0.0039	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3911730; hg19: chr18-67871343; COSMIC: COSV107305893; COSMIC: COSV107305893;