rs318240757

Positions:

• chr18-70135273-T-A
• chr18-70135273-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_173630.4(RTTN):​c.2796A>T​(p.Leu932Phe) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-70135273-T-A is Pathogenic according to our data. Variant chr18-70135273-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 68847.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-70135273-T-A is described in Lovd as [Pathogenic]. Variant chr18-70135273-T-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2603624). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.2796A>T	p.Leu932Phe	missense_variant	22/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.2796A>T	p.Leu932Phe	missense_variant	22/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA WITH SEIZURES Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 07, 2012

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.65	.;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.16	.;T;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.28		Gain of catalytic residue at L932 (P = 0.0255);Gain of catalytic residue at L932 (P = 0.0255);.;
MVP		0.53
MPC		0.43
ClinPred		0.60	D
GERP RS		3.7
Varity_R		0.10
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs318240757; hg19: chr18-67802509;