NM_173630.4:c.488-923C>T

Variant names:

• chr18-70200427-G-A
• rs4891825
• NM_173630.4:c.488-923C>T

Variant summary

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

The NM_173630.4(RTTN):​c.488-923C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 152,066 control chromosomes in the GnomAD database, including 46,384 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 0.72 (46384 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 13 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.488-923C>T		intron_variant	Intron 4 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.488-923C>T		intron_variant	Intron 4 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109468 AN: 151948 Hom.: 46377 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.914

Gnomad OTH AF: 0.763

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

GnomAD4 genome AF: 0.720 AC: 109494 AN: 152066 Hom.: 46384 Cov.: 32 AF XY: 0.726 AC XY: 53955 AN XY: 74348

African (AFR) AF: 0.236 AC: 9760 AN: 41370

American (AMR) AF: 0.835 AC: 12779 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3139 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5154 AN: 5172

South Asian (SAS) AF: 0.889 AC: 4294 AN: 4830

European-Finnish (FIN) AF: 0.904 AC: 9579 AN: 10602

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.914 AC: 62153 AN: 68004

Other (OTH) AF: 0.766 AC: 1617 AN: 2112

Alfa AF: 0.844 Hom.: 171313

Bravo AF: 0.691

Asia WGS AF: 0.887 AC: 3083 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.64
PhyloP100		-0.34
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: rs4891825; hg19: chr18-67867663;