rs12953952

Variant names:

• chr18-70070691-A-G
• rs12953952
• NM_173630.4:c.4653+3215T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173630.4(RTTN):​c.4653+3215T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 152,132 control chromosomes in the GnomAD database, including 49,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (49570 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.453
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4653+3215T>C		intron_variant	Intron 34 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.4653+3215T>C		intron_variant	Intron 34 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113597 AN: 152014 Hom.: 49563 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.922

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.939

Gnomad OTH AF: 0.798

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.747 AC: 113613 AN: 152132 Hom.: 49570 Cov.: 32 AF XY: 0.754 AC XY: 56066 AN XY: 74380

African (AFR) AF: 0.256 AC: 10618 AN: 41444

American (AMR) AF: 0.884 AC: 13511 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 3266 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5160 AN: 5170

South Asian (SAS) AF: 0.922 AC: 4451 AN: 4826

European-Finnish (FIN) AF: 0.942 AC: 10002 AN: 10618

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.939 AC: 63872 AN: 68004

Other (OTH) AF: 0.801 AC: 1686 AN: 2106

Alfa AF: 0.854 Hom.: 20361

Bravo AF: 0.720

Asia WGS AF: 0.903 AC: 3139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.81
PhyloP100		0.45
Mutation Taster		=100/0	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: rs12953952; hg19: chr18-67737927;