chr18-70006461-C-T

Variant names:

• chr18-70006461-C-T
• rs34989098
• NM_173630.4:c.6445G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173630.4(RTTN):​c.6445G>A​(p.Ala2149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,800 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0061 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (63 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.376
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00667727).
• BP6: Variant 18-70006461-C-T is Benign according to our data. Variant chr18-70006461-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130194.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00609 (927/152336) while in subpopulation AMR AF = 0.00921 (141/15304). AF 95% confidence interval is 0.00846. There are 5 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.6445G>A	p.Ala2149Thr	missense	Exon 47 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.3709G>A	p.Ala1237Thr	missense	Exon 46 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.6445G>A	p.Ala2149Thr	missense	Exon 47 of 49	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*4759G>A		non_coding_transcript_exon	Exon 46 of 48	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*3685G>A		non_coding_transcript_exon	Exon 41 of 43	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 926 AN: 152218 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00577 AC: 1438 AN: 249042 AF XY: 0.00604

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00941

Gnomad NFE exome AF: 0.00853

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00621 AC: 9077 AN: 1461464 Hom.: 63 Cov.: 29 AF XY: 0.00631 AC XY: 4587 AN XY: 727056

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00472 AC: 211 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86258

European-Finnish (FIN) AF: 0.00968 AC: 517 AN: 53410

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5764

European-Non Finnish (NFE) AF: 0.00699 AC: 7765 AN: 1111660

Other (OTH) AF: 0.00533 AC: 322 AN: 60380

GnomAD4 genome AF: 0.00609 AC: 927 AN: 152336 Hom.: 5 Cov.: 32 AF XY: 0.00589 AC XY: 439 AN XY: 74506

African (AFR) AF: 0.000914 AC: 38 AN: 41578

American (AMR) AF: 0.00921 AC: 141 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00905 AC: 616 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00736 Hom.: 9

Bravo AF: 0.00557

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000815 AC: 3

ESP6500EA AF: 0.00808 AC: 66

ExAC AF: 0.00571 AC: 690

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 07, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTTN: BP4, BS2

Microcephalic primordial dwarfism due to RTTN deficiency Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Possible pathogenicity based on finding it once in our laboratory in trans with another missense variant in a 3-year-old female with microcephaly, craniosynostosis, dysmorphisms, fused labia, absence seizures, failure to thrive. However, allele frequency is high, and homozygotes have been found in controls.

not specified Benign:1

May 05, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Mar 19, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

RTTN-related disorder Benign:1

Sep 12, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.9
DANN	Benign	0.87
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.38
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.059
Sift	Benign	0.64	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.095
MVP		0.095
MPC		0.068
ClinPred		0.0043	T
GERP RS		1.1
Varity_R		0.034
gMVP		0.043
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34989098; hg19: chr18-67673697;