rs62089120

Variant names:

• chr18-70088098-G-A
• rs62089120
• NM_173630.4:c.4193C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173630.4(RTTN):​c.4193C>T​(p.Thr1398Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,613,870 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (16 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.248
• Publications: 7 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068203807).
• BP6: Variant 18-70088098-G-A is Benign according to our data. Variant chr18-70088098-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436608.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (318/152288) while in subpopulation NFE AF = 0.00412 (280/68014). AF 95% confidence interval is 0.00372. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.4193C>T	p.Thr1398Met	missense	Exon 31 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.1457C>T	p.Thr486Met	missense	Exon 30 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.4193C>T	p.Thr1398Met	missense	Exon 31 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*2507C>T		non_coding_transcript_exon	Exon 30 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.*1464C>T		non_coding_transcript_exon	Exon 25 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00183 AC: 455 AN: 249216 AF XY: 0.00182

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00355 AC: 5191 AN: 1461582 Hom.: 16 Cov.: 31 AF XY: 0.00346 AC XY: 2519 AN XY: 727096

African (AFR) AF: 0.000568 AC: 19 AN: 33464

American (AMR) AF: 0.000202 AC: 9 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00444 AC: 4939 AN: 1111842

Other (OTH) AF: 0.00311 AC: 188 AN: 60388

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74460

African (AFR) AF: 0.000698 AC: 29 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00204

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00131 AC: 5

ESP6500EA AF: 0.00523 AC: 43

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00426

EpiControl AF: 0.00320

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.16
Sift	Benign	0.25	T
Sift4G	Benign	0.15	T
Polyphen		0.93	P
Vest4		0.24
MVP		0.44
MPC		0.10
ClinPred		0.016	T
GERP RS		3.4
Varity_R		0.022
gMVP		0.20
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62089120; hg19: chr18-67755334;