NM_173630.4:c.1921A>G

Variant names:

• chr18-70166070-T-C
• rs117502718
• NM_173630.4:c.1921A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173630.4(RTTN):​c.1921A>G​(p.Ile641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,613,612 control chromosomes in the GnomAD database, including 93 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 0.0060 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (90 hom.)
• Consequence: RTTN NM_173630.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.878
• Publications: 8 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 (MetaRNN=0.004217416).
• BP6: Variant 18-70166070-T-C is Benign according to our data. Variant chr18-70166070-T-C is described in ClinVar as Benign. ClinVar VariationId is 130168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00597 (909/152336) while in subpopulation NFE AF = 0.00924 (629/68038). AF 95% confidence interval is 0.00865. There are 3 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1921A>G	p.Ile641Val	missense	Exon 14 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.-727A>G		5_prime_UTR	Exon 14 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.1921A>G	p.Ile641Val	missense	Exon 14 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.*324A>G		non_coding_transcript_exon	Exon 14 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.1291A>G		non_coding_transcript_exon	Exon 9 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 911 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00924

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00672 AC: 1673 AN: 248946 AF XY: 0.00723

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00640

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.00931 AC: 13598 AN: 1461276 Hom.: 90 Cov.: 30 AF XY: 0.00930 AC XY: 6761 AN XY: 726940

African (AFR) AF: 0.00209 AC: 70 AN: 33466

American (AMR) AF: 0.00239 AC: 107 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 156 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0100 AC: 863 AN: 86180

European-Finnish (FIN) AF: 0.00685 AC: 366 AN: 53396

Middle Eastern (MID) AF: 0.0236 AC: 136 AN: 5764

European-Non Finnish (NFE) AF: 0.0102 AC: 11345 AN: 1111648

Other (OTH) AF: 0.00919 AC: 555 AN: 60372

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74496

African (AFR) AF: 0.00221 AC: 92 AN: 41578

American (AMR) AF: 0.00386 AC: 59 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00924 AC: 629 AN: 68038

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00825 Hom.: 15

Bravo AF: 0.00579

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00289 AC: 11

ESP6500EA AF: 0.00933 AC: 77

ExAC AF: 0.00675 AC: 816

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.00999

EpiControl AF: 0.00836

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	RTTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.0
DANN	Benign	0.92
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.88
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.018
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.0040	B
Vest4		0.12
MVP		0.16
MPC		0.061
ClinPred		0.0012	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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: rs117502718; hg19: chr18-67833306;