18-70004903-T-C

Variant names:

• chr18-70004903-T-C
• rs12968403
• NM_173630.4:c.6595+295A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173630.4(RTTN):​c.6595+295A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 152,246 control chromosomes in the GnomAD database, including 55,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.81 (55186 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.232

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 18-70004903-T-C is Benign according to our data. Variant chr18-70004903-T-C is described in ClinVar as [Benign]. Clinvar id is 684155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.6595+295A>G		intron_variant	Intron 48 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.6595+295A>G		intron_variant	Intron 48 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123461 AN: 152128 Hom.: 55176 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.978

Gnomad OTH AF: 0.846

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

GnomAD4 genome AF: 0.811 AC: 123504 AN: 152246 Hom.: 55186 Cov.: 32 AF XY: 0.817 AC XY: 60846 AN XY: 74454

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.913

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.971

Gnomad4 FIN AF: 0.990

Gnomad4 NFE AF: 0.978

Gnomad4 OTH AF: 0.848

Alfa AF: 0.905 Hom.: 18056

Bravo AF: 0.785

Asia WGS AF: 0.931 AC: 3234 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs12968403; hg19: chr18-67672139;