18-70051452-A-G

Variant names:

• chr18-70051452-A-G
• rs4891392
• NM_173630.4:c.5282T>C

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.5282T>C​(p.Phe1761Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,613,786 control chromosomes in the GnomAD database, including 717,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (53926 hom., cov: 33)
  • Exomes 𝑓: 0.95 (663174 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.268011E-7).
• BP6: Variant 18-70051452-A-G is Benign according to our data. Variant chr18-70051452-A-G is described in ClinVar as Benign. ClinVar VariationId is 130188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	NM_173630.4	MANE Select	c.5282T>C	p.Phe1761Ser	missense	Exon 39 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.2546T>C	p.Phe849Ser	missense	Exon 38 of 48	NP_001305449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTTN	ENST00000640769.2	TSL:2 MANE Select	c.5282T>C	p.Phe1761Ser	missense	Exon 39 of 49	ENSP00000491507.1
	RTTN	ENST00000581161.5	TSL:1	n.*3596T>C		non_coding_transcript_exon	Exon 38 of 48	ENSP00000462926.1
	RTTN	ENST00000583043.5	TSL:1	n.*2553T>C		non_coding_transcript_exon	Exon 33 of 43	ENSP00000462733.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122676 AN: 152072 Hom.: 53904 Cov.: 33

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.894

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.966

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.841

GnomAD2 exomes AF: 0.927 AC: 231014 AN: 249198 AF XY: 0.936

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.956

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.959

Gnomad NFE exome AF: 0.961

Gnomad OTH exome AF: 0.939

GnomAD4 exome AF: 0.949 AC: 1386540 AN: 1461596 Hom.: 663174 Cov.: 45 AF XY: 0.951 AC XY: 691320 AN XY: 727110

African (AFR) AF: 0.403 AC: 13480 AN: 33442

American (AMR) AF: 0.942 AC: 42092 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 24969 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39676 AN: 39690

South Asian (SAS) AF: 0.963 AC: 83023 AN: 86242

European-Finnish (FIN) AF: 0.960 AC: 51297 AN: 53416

Middle Eastern (MID) AF: 0.893 AC: 5149 AN: 5766

European-Non Finnish (NFE) AF: 0.963 AC: 1070909 AN: 1111850

Other (OTH) AF: 0.927 AC: 55945 AN: 60382

GnomAD4 genome AF: 0.807 AC: 122742 AN: 152190 Hom.: 53926 Cov.: 33 AF XY: 0.812 AC XY: 60422 AN XY: 74406

African (AFR) AF: 0.420 AC: 17425 AN: 41450

American (AMR) AF: 0.907 AC: 13885 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3311 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5175 AN: 5178

South Asian (SAS) AF: 0.967 AC: 4665 AN: 4826

European-Finnish (FIN) AF: 0.960 AC: 10184 AN: 10612

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.959 AC: 65253 AN: 68032

Other (OTH) AF: 0.843 AC: 1780 AN: 2112

Alfa AF: 0.910 Hom.: 218532

Bravo AF: 0.783

TwinsUK AF: 0.960 AC: 3558

ALSPAC AF: 0.969 AC: 3733

ESP6500AA AF: 0.458 AC: 1758

ESP6500EA AF: 0.962 AC: 7961

ExAC AF: 0.918 AC: 110917

Asia WGS AF: 0.941 AC: 3271 AN: 3478

EpiCase AF: 0.959

EpiControl AF: 0.960

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Microcephalic primordial dwarfism due to RTTN deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.025
DANN	Benign	0.58
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N
PhyloP100		-1.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.018
Sift	Benign	0.98	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.12
ClinPred		0.0067	T
GERP RS		-1.2
Varity_R		0.048
gMVP		0.15
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: rs4891392; hg19: chr18-67718688; COSMIC: COSV107305892;