18-70004977-A-G

Position:

• chr18-70004977-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_173630.4(RTTN):​c.6595+221T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 152,368 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.011 (20 hom., cov: 32)
• Consequence: RTTN NM_173630.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.863

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-70004977-A-G is Benign according to our data. Variant chr18-70004977-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1206939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0106 (1620/152368) while in subpopulation SAS AF= 0.0442 (213/4818). AF 95% confidence interval is 0.0393. There are 20 homozygotes in gnomad4. There are 762 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTTN	NM_173630.4	c.6595+221T>C		intron_variant		ENST00000640769.2	NP_775901.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTTN	ENST00000640769.2	c.6595+221T>C		intron_variant		2	NM_173630.4	ENSP00000491507	P1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1617 AN: 152250 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00909

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

GnomAD4 genome AF: 0.0106 AC: 1620 AN: 152368 Hom.: 20 Cov.: 32 AF XY: 0.0102 AC XY: 762 AN XY: 74512

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00973

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0442

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0129 Hom.: 2

Bravo AF: 0.0100

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs150138947; hg19: chr18-67672213;