chr18-70004509-T-C

Position:

• chr18-70004509-T-C

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.6596-273A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 152,120 control chromosomes in the GnomAD database, including 64,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.91 (64592 hom., cov: 30)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.88

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=-0.95).
• BP6: Variant 18-70004509-T-C is Benign according to our data. Variant chr18-70004509-T-C is described in ClinVar as [Benign]. Clinvar id is 684156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.6596-273A>G		intron_variant		ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.6596-273A>G		intron_variant		2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.915 AC: 139089 AN: 152002 Hom.: 64564 Cov.: 30

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.951

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.982

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.926

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

GnomAD4 genome AF: 0.915 AC: 139172 AN: 152120 Hom.: 64592 Cov.: 30 AF XY: 0.917 AC XY: 68154 AN XY: 74350

Gnomad4 AFR AF: 0.737

Gnomad4 AMR AF: 0.951

Gnomad4 ASJ AF: 0.976

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.983

Gnomad4 FIN AF: 0.994

Gnomad4 NFE AF: 0.988

Gnomad4 OTH AF: 0.926

Alfa AF: 0.949 Hom.: 8191

Bravo AF: 0.903

Asia WGS AF: 0.972 AC: 3354 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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	-0.95
CADD	Benign	0.020
DANN	Benign	0.60

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: rs7241642; hg19: chr18-67671745;