chr18-70086694-TAAAAAAAAAAAAA-T

Variant names:

• chr18-70086694-TAAAAAAAAAAAAA-T
• rs531741265
• NM_173630.4:c.4303-23_4303-11delTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_173630.4(RTTN):​c.4303-23_4303-11delTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 417,648 control chromosomes in the GnomAD database, including 44 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (36 hom., cov: 0)
  • Exomes 𝑓: 0.0076 (44 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.4303-23_4303-11delTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.4303-23_4303-11delTTTTTTTTTTTTT		intron_variant	Intron 31 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 1615 AN: 68218 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00342

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.00185

Gnomad SAS AF: 0.00461

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00926

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.00760 AC: 3173 AN: 417648 Hom.: 44 AF XY: 0.00700 AC XY: 1577 AN XY: 225140

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

African (AFR) AF: 0.0273 AC: 188 AN: 6878

American (AMR) AF: 0.00640 AC: 113 AN: 17668

Ashkenazi Jewish (ASJ) AF: 0.00711 AC: 83 AN: 11672

East Asian (EAS) AF: 0.00322 AC: 85 AN: 26432

South Asian (SAS) AF: 0.00261 AC: 97 AN: 37110

European-Finnish (FIN) AF: 0.0112 AC: 332 AN: 29518

Middle Eastern (MID) AF: 0.00943 AC: 14 AN: 1484

European-Non Finnish (NFE) AF: 0.00769 AC: 2052 AN: 266774

Other (OTH) AF: 0.0104 AC: 209 AN: 20112

⚠️ 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: 0.0237 AC: 1615 AN: 68246 Hom.: 36 Cov.: 0 AF XY: 0.0227 AC XY: 687 AN XY: 30238

African (AFR) AF: 0.0454 AC: 671 AN: 14786

American (AMR) AF: 0.0203 AC: 111 AN: 5456

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 25 AN: 2146

East Asian (EAS) AF: 0.00185 AC: 4 AN: 2158

South Asian (SAS) AF: 0.00464 AC: 7 AN: 1510

European-Finnish (FIN) AF: 0.0372 AC: 43 AN: 1156

Middle Eastern (MID) AF: 0.00962 AC: 1 AN: 104

European-Non Finnish (NFE) AF: 0.0185 AC: 731 AN: 39498

Other (OTH) AF: 0.0236 AC: 20 AN: 848

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;