rs200600259

chr18-70145738-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_173630.4(RTTN):c.2355T>C(p.Ser785=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,613,364 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: RTTN NM_173630.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.30

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 18-70145738-A-G is Benign according to our data. Variant chr18-70145738-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212078.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000276 (42/152262) while in subpopulation AMR AF= 0.000654 (10/15284). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTTN	NM_173630.4	c.2355T>C	p.Ser785=	synonymous_variant	18/49	ENST00000640769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTTN	ENST00000640769.2	c.2355T>C	p.Ser785=	synonymous_variant	18/49	2	NM_173630.4	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 248684 Hom.: 0 AF XY: 0.000208 AC XY: 28 AN XY: 134928

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000352 AC: 514 AN: 1461102 Hom.: 1 Cov.: 31 AF XY: 0.000319 AC XY: 232 AN XY: 726838

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000427

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74448

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000384

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 11, 2015

- -

RTTN-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	8.5
Dann	Benign	0.57

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: rs200600259; hg19: chr18-67812974;