NM_173630.4:c.2309+12G>A

Variant names:

• chr18-70148889-C-T
• rs144279235
• NM_173630.4:c.2309+12G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173630.4(RTTN):​c.2309+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,612,854 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (41 hom.)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.09

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-70148889-C-T is Benign according to our data. Variant chr18-70148889-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 385924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-70148889-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00428 (651/152256) while in subpopulation AMR AF= 0.00641 (98/15282). AF 95% confidence interval is 0.0058. There are 1 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTTN	NM_173630.4	c.2309+12G>A		intron_variant	Intron 17 of 48	ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.2309+12G>A		intron_variant	Intron 17 of 48	2	NM_173630.4	ENSP00000491507.1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00465 AC: 1157 AN: 248820 Hom.: 3 AF XY: 0.00442 AC XY: 597 AN XY: 134970

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00588

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00624 AC: 9117 AN: 1460598 Hom.: 41 Cov.: 30 AF XY: 0.00593 AC XY: 4306 AN XY: 726612

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00649

Gnomad4 ASJ exome AF: 0.00936

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00224

Gnomad4 FIN exome AF: 0.000731

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.00549

GnomAD4 genome AF: 0.00428 AC: 651 AN: 152256 Hom.: 1 Cov.: 31 AF XY: 0.00382 AC XY: 284 AN XY: 74426

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00618 Hom.: 1

Bravo AF: 0.00462

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 11, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144279235; hg19: chr18-67816125;