18-70166989-C-T

Variant names:

• chr18-70166989-C-T
• rs775277800
• NM_173630.4:c.1732G>A

Variant summary

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

The NM_173630.4(RTTN):​c.1732G>A​(p.Ala578Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28064278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.1732G>A	p.Ala578Thr	missense_variant	Exon 13 of 49	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.1732G>A	p.Ala578Thr	missense_variant	Exon 13 of 49	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248982 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135080

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461462 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	.;N;.
REVEL	Benign	0.22
Sift	Uncertain	0.0060	.;D;.
Sift4G	Uncertain	0.0070	.;D;.
Polyphen		0.84	P;.;.
Vest4		0.83
MutPred		0.31		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;
MVP		0.37
MPC		0.33
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.22
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;