chr18-70005258-C-G

Variant names:

• chr18-70005258-C-G
• rs587780444
• NM_173630.4:c.6535G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_173630.4(RTTN):​c.6535G>C​(p.Ala2179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,459,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.66
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09393552).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000274 (40/1459962) while in subpopulation SAS AF = 0.000407 (35/86080). AF 95% confidence interval is 0.0003. There are 1 homozygotes in GnomAdExome4. There are 32 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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.6535G>C	p.Ala2179Pro	missense	Exon 48 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.3799G>C	p.Ala1267Pro	missense	Exon 47 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.6535G>C	p.Ala2179Pro	missense	Exon 48 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*4849G>C		non_coding_transcript_exon	Exon 47 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.*3775G>C		non_coding_transcript_exon	Exon 42 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000685 AC: 17 AN: 248290 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459962 Hom.: 1 Cov.: 29 AF XY: 0.0000441 AC XY: 32 AN XY: 726340

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.000407 AC: 35 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110896

Other (OTH) AF: 0.0000332 AC: 2 AN: 60316

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.058	T
Sift4G	Uncertain	0.047	D
Polyphen		0.47	P
Vest4		0.58
MutPred		0.38		Gain of glycosylation at A2179 (P = 0.0138)
MVP		0.16
MPC		0.13
ClinPred		0.10	T
GERP RS		3.1
Varity_R		0.26
gMVP		0.54
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs587780444; hg19: chr18-67672494;