chr18-70024284-A-C

Variant names:

• chr18-70024284-A-C
• rs1369290
• NM_173630.4:c.5950+438T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173630.4(RTTN):​c.5950+438T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 152,190 control chromosomes in the GnomAD database, including 51,365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (51365 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.5950+438T>G		intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.3214+438T>G		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.5950+438T>G		intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*4264+438T>G		intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*3221+438T>G		intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115615 AN: 152072 Hom.: 51360 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.956

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.958

Gnomad OTH AF: 0.813

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.760 AC: 115631 AN: 152190 Hom.: 51365 Cov.: 32 AF XY: 0.767 AC XY: 57084 AN XY: 74398

African (AFR) AF: 0.259 AC: 10735 AN: 41462

American (AMR) AF: 0.892 AC: 13655 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.956 AC: 3316 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5168 AN: 5176

South Asian (SAS) AF: 0.932 AC: 4492 AN: 4818

European-Finnish (FIN) AF: 0.972 AC: 10319 AN: 10618

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.958 AC: 65169 AN: 68026

Other (OTH) AF: 0.815 AC: 1721 AN: 2112

Alfa AF: 0.808 Hom.: 9267

Bravo AF: 0.731

Asia WGS AF: 0.909 AC: 3159 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.47
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs1369290; hg19: chr18-67691520;