rs7998

Variant names:

• chr18-70004058-C-T
• rs7998
• NM_173630.4:c.*93G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173630.4(RTTN):​c.*93G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 871,694 control chromosomes in the GnomAD database, including 3,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (464 hom., cov: 31)
  • Exomes 𝑓: 0.083 (2687 hom.)
• Consequence: RTTN NM_173630.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.78
• Publications: 5 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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 18-70004058-C-T is Benign according to our data. Variant chr18-70004058-C-T is described in ClinVar as Benign. ClinVar VariationId is 1221909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.*93G>A		3_prime_UTR	Exon 49 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.*93G>A		3_prime_UTR	Exon 48 of 48	NP_001305449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.*93G>A		3_prime_UTR	Exon 49 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*5088G>A		non_coding_transcript_exon	Exon 48 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.*4014G>A		non_coding_transcript_exon	Exon 43 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10454 AN: 152106 Hom.: 464 Cov.: 31

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0669

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0695

GnomAD4 exome AF: 0.0831 AC: 59755 AN: 719470 Hom.: 2687 Cov.: 9 AF XY: 0.0844 AC XY: 32219 AN XY: 381932

African (AFR) AF: 0.0159 AC: 299 AN: 18818

American (AMR) AF: 0.0429 AC: 1702 AN: 39712

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 1468 AN: 19908

East Asian (EAS) AF: 0.0681 AC: 2400 AN: 35250

South Asian (SAS) AF: 0.0790 AC: 5153 AN: 65190

European-Finnish (FIN) AF: 0.0686 AC: 3259 AN: 47506

Middle Eastern (MID) AF: 0.0804 AC: 339 AN: 4218

European-Non Finnish (NFE) AF: 0.0932 AC: 42250 AN: 453448

Other (OTH) AF: 0.0815 AC: 2885 AN: 35420

GnomAD4 genome AF: 0.0687 AC: 10455 AN: 152224 Hom.: 464 Cov.: 31 AF XY: 0.0681 AC XY: 5071 AN XY: 74428

African (AFR) AF: 0.0175 AC: 728 AN: 41544

American (AMR) AF: 0.0668 AC: 1021 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3472

East Asian (EAS) AF: 0.0867 AC: 449 AN: 5176

South Asian (SAS) AF: 0.0856 AC: 413 AN: 4826

European-Finnish (FIN) AF: 0.0644 AC: 682 AN: 10592

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0976 AC: 6636 AN: 68016

Other (OTH) AF: 0.0688 AC: 145 AN: 2108

Alfa AF: 0.0855 Hom.: 759

Bravo AF: 0.0636

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.033
DANN	Benign	0.66
PhyloP100		-4.8
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: rs7998; hg19: chr18-67671294; COSMIC: COSV55343661; COSMIC: COSV55343661;