rs775277800

Positions:

• chr18-70166989-C-G
• chr18-70166989-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_173630.4(RTTN):​c.1732G>C​(p.Ala578Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A578A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.06

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-70166989-C-G is Pathogenic according to our data. Variant chr18-70166989-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219186.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.1732G>C	p.Ala578Pro	missense_variant	13/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.1732G>C	p.Ala578Pro	missense_variant	13/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary microcephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 25, 2015

- -

Microcephalic primordial dwarfism due to RTTN deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.92	P;.;.
Vest4		0.97
MutPred		0.47		Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);.;
MVP		0.38
MPC		0.43
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.64
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs775277800; hg19: chr18-67834225;