18-70086692-T-G

Variant names:

• chr18-70086692-T-G
• rs199597732
• NM_173630.4:c.4303-8A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_173630.4(RTTN):​c.4303-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: RTTN NM_173630.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003186
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.734
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-70086692-T-G is Benign according to our data. Variant chr18-70086692-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3349180.Status of the report is no_assertion_criteria_provided, 0 stars.

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.4303-8A>C		splice_region intron	N/A	NP_775901.3
	RTTN	NM_001318520.2		c.1567-8A>C		splice_region 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.4303-8A>C		splice_region intron	N/A	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*2617-8A>C		splice_region intron	N/A	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*1574-8A>C		splice_region intron	N/A	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.0000555 AC: 1 AN: 18002 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000950

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000223 AC: 2 AN: 89732 AF XY: 0.0000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000224

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000196 AC: 3 AN: 152706 Hom.: 0 Cov.: 0 AF XY: 0.0000237 AC XY: 2 AN XY: 84258

⚠️ 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: 2412

American (AMR) AF: 0.00 AC: 0 AN: 8548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4968

East Asian (EAS) AF: 0.00 AC: 0 AN: 9170

South Asian (SAS) AF: 0.000138 AC: 2 AN: 14542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 462

European-Non Finnish (NFE) AF: 0.0000111 AC: 1 AN: 89768

Other (OTH) AF: 0.00 AC: 0 AN: 6370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00250614), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000555 AC: 1 AN: 18002 Hom.: 0 Cov.: 0 AF XY: 0.000126 AC XY: 1 AN XY: 7948

African (AFR) AF: 0.00 AC: 0 AN: 3816

American (AMR) AF: 0.00 AC: 0 AN: 1096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 512

East Asian (EAS) AF: 0.00 AC: 0 AN: 662

South Asian (SAS) AF: 0.00 AC: 0 AN: 592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.0000950 AC: 1 AN: 10530

Other (OTH) AF: 0.00 AC: 0 AN: 214

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

RTTN-related disorder Benign:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		-0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
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: rs199597732; hg19: chr18-67753928;