rs144279235

Variant names:

• chr18-70148889-C-T
• rs144279235
• NM_173630.4:c.2309+12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173630.4(RTTN):​c.2309+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,612,854 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (41 hom.)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.09
• Publications: 0 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 (BayesDel_noAF=-0.88).
• BP6: Variant 18-70148889-C-T is Benign according to our data. Variant chr18-70148889-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00428 (651/152256) while in subpopulation AMR AF = 0.00641 (98/15282). AF 95% confidence interval is 0.0058. There are 1 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.2309+12G>A		intron_variant	Intron 17 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.2309+12G>A		intron_variant	Intron 17 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00465 AC: 1157 AN: 248820 AF XY: 0.00442

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00588

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00624 AC: 9117 AN: 1460598 Hom.: 41 Cov.: 30 AF XY: 0.00593 AC XY: 4306 AN XY: 726612

African (AFR) AF: 0.00114 AC: 38 AN: 33418

American (AMR) AF: 0.00649 AC: 290 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00936 AC: 244 AN: 26082

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39664

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86194

European-Finnish (FIN) AF: 0.000731 AC: 39 AN: 53362

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.00717 AC: 7970 AN: 1111134

Other (OTH) AF: 0.00549 AC: 331 AN: 60322

GnomAD4 genome AF: 0.00428 AC: 651 AN: 152256 Hom.: 1 Cov.: 31 AF XY: 0.00382 AC XY: 284 AN XY: 74426

African (AFR) AF: 0.00159 AC: 66 AN: 41556

American (AMR) AF: 0.00641 AC: 98 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00629 AC: 428 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00618 Hom.: 1

Bravo AF: 0.00462

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 02, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Dec 11, 2017

GeneDx

Significance: Likely 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.79
PhyloP100		-2.1
PromoterAI		-0.028	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144279235; hg19: chr18-67816125;