chr18-70086694-TAAAAAAAAAAAA-T

Variant names:

• chr18-70086694-TAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-22_4303-11delTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_173630.4(RTTN):​c.4303-22_4303-11delTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 419,226 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (26 hom., cov: 0)
  • Exomes 𝑓: 0.00098 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.23
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 1271007.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.4303-22_4303-11delTTTTTTTTTTTT		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-22_1567-11delTTTTTTTTTTTT		intron	N/A	NP_001305449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.4303-22_4303-11delTTTTTTTTTTTT		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2617-22_*2617-11delTTTTTTTTTTTT		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1574-22_*1574-11delTTTTTTTTTTTT		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 1228 AN: 68144 Hom.: 26 Cov.: 0

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00862

Gnomad ASJ AF: 0.00140

Gnomad EAS AF: 0.000463

Gnomad SAS AF: 0.000659

Gnomad FIN AF: 0.00260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.000978 AC: 410 AN: 419226 Hom.: 1 AF XY: 0.000859 AC XY: 194 AN XY: 225974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0131 AC: 90 AN: 6894

American (AMR) AF: 0.000790 AC: 14 AN: 17718

Ashkenazi Jewish (ASJ) AF: 0.000940 AC: 11 AN: 11708

East Asian (EAS) AF: 0.000452 AC: 12 AN: 26520

South Asian (SAS) AF: 0.000377 AC: 14 AN: 37156

European-Finnish (FIN) AF: 0.000809 AC: 24 AN: 29652

Middle Eastern (MID) AF: 0.00268 AC: 4 AN: 1492

European-Non Finnish (NFE) AF: 0.000769 AC: 206 AN: 267852

Other (OTH) AF: 0.00173 AC: 35 AN: 20234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0180 AC: 1230 AN: 68172 Hom.: 26 Cov.: 0 AF XY: 0.0183 AC XY: 554 AN XY: 30204

African (AFR) AF: 0.0695 AC: 1024 AN: 14744

American (AMR) AF: 0.00861 AC: 47 AN: 5456

Ashkenazi Jewish (ASJ) AF: 0.00140 AC: 3 AN: 2146

East Asian (EAS) AF: 0.000463 AC: 1 AN: 2158

South Asian (SAS) AF: 0.000662 AC: 1 AN: 1510

European-Finnish (FIN) AF: 0.00260 AC: 3 AN: 1152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 104

European-Non Finnish (NFE) AF: 0.00357 AC: 141 AN: 39470

Other (OTH) AF: 0.0118 AC: 10 AN: 848

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs531741265; hg19: chr18-67753930;