NM_173630.4:c.2055+7C>T

Variant names:

• chr18-70150601-G-A
• rs117843366
• NM_173630.4:c.2055+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173630.4(RTTN):​c.2055+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,610,260 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 33)
  • Exomes 𝑓: 0.021 (411 hom.)
• Consequence: RTTN NM_173630.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001870
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.400
• Publications: 3 publications found

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]

RTTN Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism due to RTTN deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-70150601-G-A is Benign according to our data. Variant chr18-70150601-G-A is described in ClinVar as Benign. ClinVar VariationId is 130169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2513/152186) while in subpopulation NFE AF = 0.0252 (1711/68004). AF 95% confidence interval is 0.0242. There are 40 homozygotes in GnomAd4. There are 1198 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.2055+7C>T		splice_region_variant, intron_variant	Intron 15 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.2055+7C>T		splice_region_variant, intron_variant	Intron 15 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2511 AN: 152068 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0158 AC: 3941 AN: 248682 AF XY: 0.0155

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0215 AC: 31279 AN: 1458074 Hom.: 411 Cov.: 29 AF XY: 0.0208 AC XY: 15090 AN XY: 725574

African (AFR) AF: 0.00431 AC: 144 AN: 33374

American (AMR) AF: 0.0176 AC: 785 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 369 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86126

European-Finnish (FIN) AF: 0.0116 AC: 620 AN: 53378

Middle Eastern (MID) AF: 0.00592 AC: 34 AN: 5742

European-Non Finnish (NFE) AF: 0.0255 AC: 28263 AN: 1109038

Other (OTH) AF: 0.0171 AC: 1033 AN: 60248

GnomAD4 genome AF: 0.0165 AC: 2513 AN: 152186 Hom.: 40 Cov.: 33 AF XY: 0.0161 AC XY: 1198 AN XY: 74408

African (AFR) AF: 0.00544 AC: 226 AN: 41534

American (AMR) AF: 0.0227 AC: 347 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0252 AC: 1711 AN: 68004

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0219 Hom.: 68

Bravo AF: 0.0170

Asia WGS AF: 0.00202 AC: 7 AN: 3472

EpiCase AF: 0.0251

EpiControl AF: 0.0271

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Feb 11, 2016

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, outside splice consensus -

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.32
PhyloP100		0.40
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs117843366; hg19: chr18-67817837;