rs4891392

Variant names:

• chr18-70051452-A-C
• rs4891392
• NM_173630.4:c.5282T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-70051452-A-C
• chr18-70051452-A-G
• chr18-70051452-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173630.4(RTTN):​c.5282T>G​(p.Phe1761Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1761S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 28 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0724031).

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.5282T>G	p.Phe1761Cys	missense	Exon 39 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.2546T>G	p.Phe849Cys	missense	Exon 38 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.5282T>G	p.Phe1761Cys	missense	Exon 39 of 49	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*3596T>G		non_coding_transcript_exon	Exon 38 of 48	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*2553T>G		non_coding_transcript_exon	Exon 33 of 43	ENSP00000462733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.5
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.032
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.30	B
Vest4		0.19
MutPred		0.37		Gain of catalytic residue at P1760 (P = 0.0103)
MVP		0.16
MPC		0.19
ClinPred		0.14	T
GERP RS		-1.2
Varity_R		0.046
gMVP		0.19

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: rs4891392; hg19: chr18-67718688;