18-70086694-TAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

• chr18-70086694-TAAAAAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-27_4303-11delTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_173630.4(RTTN):​c.4303-27_4303-11delTTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 414,016 control chromosomes in the GnomAD database, including 402 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 0.00023 (0 hom., cov: 0)
  • Exomes 𝑓: 0.085 (402 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 18-70086694-TAAAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr18-70086694-TAAAAAAAAAAAAAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 516914.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 402 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.4303-27_4303-11delTTTTTTTTTTTTTTTTT		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-27_1567-11delTTTTTTTTTTTTTTTTT		intron	N/A	NP_001305449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.4303-27_4303-11delTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2617-27_*2617-11delTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1574-27_*1574-11delTTTTTTTTTTTTTTTTT		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.000220 AC: 15 AN: 68180 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000101

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0208 AC: 1895 AN: 90912 AF XY: 0.0185

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0460

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.0476

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0846 AC: 35019 AN: 414016 Hom.: 402 AF XY: 0.0841 AC XY: 18777 AN XY: 223208

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

African (AFR) AF: 0.0657 AC: 450 AN: 6852

American (AMR) AF: 0.0797 AC: 1396 AN: 17508

Ashkenazi Jewish (ASJ) AF: 0.0788 AC: 909 AN: 11534

East Asian (EAS) AF: 0.132 AC: 3437 AN: 25950

South Asian (SAS) AF: 0.0732 AC: 2698 AN: 36842

European-Finnish (FIN) AF: 0.0696 AC: 2047 AN: 29394

Middle Eastern (MID) AF: 0.0921 AC: 136 AN: 1476

European-Non Finnish (NFE) AF: 0.0832 AC: 22008 AN: 264554

Other (OTH) AF: 0.0974 AC: 1938 AN: 19906

⚠️ 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: 0.000235 AC: 16 AN: 68208 Hom.: 0 Cov.: 0 AF XY: 0.000199 AC XY: 6 AN XY: 30224

African (AFR) AF: 0.000744 AC: 11 AN: 14776

American (AMR) AF: 0.000183 AC: 1 AN: 5456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2146

East Asian (EAS) AF: 0.00 AC: 0 AN: 2158

South Asian (SAS) AF: 0.00 AC: 0 AN: 1510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1152

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

European-Non Finnish (NFE) AF: 0.000101 AC: 4 AN: 39474

Other (OTH) AF: 0.00 AC: 0 AN: 848

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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;