NM_173630.4:c.5032-1240A>G

Variant names:

• chr18-70055524-T-C
• rs11876150
• NM_173630.4:c.5032-1240A>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.5032-1240A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 152,038 control chromosomes in the GnomAD database, including 49,530 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 0.75 (49530 hom., cov: 30)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.359
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.5032-1240A>G		intron_variant	Intron 37 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.5032-1240A>G		intron_variant	Intron 37 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113491 AN: 151922 Hom.: 49523 Cov.: 30

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.922

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.939

Gnomad OTH AF: 0.798

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

GnomAD4 genome AF: 0.747 AC: 113507 AN: 152038 Hom.: 49530 Cov.: 30 AF XY: 0.754 AC XY: 56006 AN XY: 74318

African (AFR) AF: 0.255 AC: 10582 AN: 41418

American (AMR) AF: 0.883 AC: 13494 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3266 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5155 AN: 5164

South Asian (SAS) AF: 0.923 AC: 4445 AN: 4816

European-Finnish (FIN) AF: 0.942 AC: 9970 AN: 10584

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.939 AC: 63862 AN: 68000

Other (OTH) AF: 0.800 AC: 1689 AN: 2110

Alfa AF: 0.819 Hom.: 6489

Bravo AF: 0.720

Asia WGS AF: 0.904 AC: 3142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.98
DANN	Benign	0.39
PhyloP100		-0.36
Mutation Taster		=99/1	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: rs11876150; hg19: chr18-67722760; COSMIC: COSV55353617; COSMIC: COSV55353617;