chr18-70086694-TAAAA-T

Variant names:

• chr18-70086694-TAAAA-T
• rs531741265
• NM_173630.4:c.4303-14_4303-11delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173630.4(RTTN):​c.4303-14_4303-11delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000953 in 419,608 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000095 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.927
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4303-14_4303-11delTTTT		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-14_1567-11delTTTT		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.4303-14_4303-11delTTTT		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2617-14_*2617-11delTTTT		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1574-14_*1574-11delTTTT		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.000645 AC: 44 AN: 68166 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000550

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: 0.0000253

Gnomad OTH AF: 0.00120

GnomAD4 exome AF: 0.00000953 AC: 4 AN: 419608 Hom.: 0 AF XY: 0.00000884 AC XY: 2 AN XY: 226196

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

African (AFR) AF: 0.00 AC: 0 AN: 6930

American (AMR) AF: 0.00 AC: 0 AN: 17750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11714

East Asian (EAS) AF: 0.00 AC: 0 AN: 26534

South Asian (SAS) AF: 0.00 AC: 0 AN: 37168

European-Finnish (FIN) AF: 0.0000337 AC: 1 AN: 29676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1494

European-Non Finnish (NFE) AF: 0.00000373 AC: 1 AN: 268096

Other (OTH) AF: 0.0000988 AC: 2 AN: 20246

⚠️ 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: 0.000645 AC: 44 AN: 68194 Hom.: 0 Cov.: 0 AF XY: 0.000529 AC XY: 16 AN XY: 30222

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

African (AFR) AF: 0.00264 AC: 39 AN: 14764

American (AMR) AF: 0.000550 AC: 3 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: 0.0000253 AC: 1 AN: 39472

Other (OTH) AF: 0.00118 AC: 1 AN: 848

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.93

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: rs531741265; hg19: chr18-67753930;