18-70020730-C-A

Variant names:

• chr18-70020730-C-A
• rs145976466
• NM_173630.4:c.6038G>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.6038G>T​(p.Cys2013Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,614,080 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2013Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (76 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.72
• Publications: 6 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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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 (MetaRNN=0.005443305).
• BP6: Variant 18-70020730-C-A is Benign according to our data. Variant chr18-70020730-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130190.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 = 0.0054 (822/152344) while in subpopulation NFE AF = 0.00839 (571/68034). AF 95% confidence interval is 0.00782. There are 4 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.6038G>T	p.Cys2013Phe	missense	Exon 45 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.3302G>T	p.Cys1101Phe	missense	Exon 44 of 48	NP_001305449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.6038G>T	p.Cys2013Phe	missense	Exon 45 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*4352G>T		non_coding_transcript_exon	Exon 44 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.*3309G>T		non_coding_transcript_exon	Exon 39 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 822 AN: 152226 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00839

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00661 AC: 1646 AN: 248958 AF XY: 0.00741

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00837

Gnomad OTH exome AF: 0.00711

GnomAD4 exome AF: 0.00793 AC: 11587 AN: 1461736 Hom.: 76 Cov.: 31 AF XY: 0.00807 AC XY: 5869 AN XY: 727192

African (AFR) AF: 0.00170 AC: 57 AN: 33476

American (AMR) AF: 0.00470 AC: 210 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0129 AC: 1112 AN: 86256

European-Finnish (FIN) AF: 0.00185 AC: 99 AN: 53420

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5768

European-Non Finnish (NFE) AF: 0.00851 AC: 9463 AN: 1111884

Other (OTH) AF: 0.00671 AC: 405 AN: 60394

GnomAD4 genome AF: 0.00540 AC: 822 AN: 152344 Hom.: 4 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74508

African (AFR) AF: 0.00115 AC: 48 AN: 41572

American (AMR) AF: 0.00771 AC: 118 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00839 AC: 571 AN: 68034

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00724 Hom.: 19

Bravo AF: 0.00535

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.00834 AC: 69

ExAC AF: 0.00707 AC: 854

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00917

EpiControl AF: 0.00806

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	RTTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.030	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.37
MVP		0.51
MPC		0.17
ClinPred		0.0078	T
GERP RS		6.1
Varity_R		0.13
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs145976466; hg19: chr18-67687966; COSMIC: COSV105050690; COSMIC: COSV105050690;