NM_173630.4:c.4144-440T>C

Variant names:

• chr18-70088587-A-G
• rs10513991
• NM_173630.4:c.4144-440T>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.4144-440T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 152,254 control chromosomes in the GnomAD database, including 789 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 0.072 (789 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.334
• Publications: 1 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 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.4144-440T>C		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1408-440T>C		intron	N/A	NP_001305449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.4144-440T>C		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2458-440T>C		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1415-440T>C		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10883 AN: 152136 Hom.: 787 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0655

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

GnomAD4 genome AF: 0.0716 AC: 10898 AN: 152254 Hom.: 789 Cov.: 32 AF XY: 0.0696 AC XY: 5181 AN XY: 74450

African (AFR) AF: 0.178 AC: 7385 AN: 41524

American (AMR) AF: 0.0578 AC: 884 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0325 AC: 157 AN: 4832

European-Finnish (FIN) AF: 0.0383 AC: 406 AN: 10604

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1760 AN: 68018

Other (OTH) AF: 0.0648 AC: 137 AN: 2114

Alfa AF: 0.0479 Hom.: 131

Bravo AF: 0.0791

Asia WGS AF: 0.0260 AC: 91 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.61
PhyloP100		0.33
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: rs10513991; hg19: chr18-67755823;