rs58913700

Variant names:

• chr18-70196614-T-TCTC
• rs58913700
• NM_173630.4:c.725_727dupGAG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_173630.4(RTTN):​c.725_727dupGAG​(p.Gly242dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,613,158 control chromosomes in the GnomAD database, including 794,838 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70117 hom., cov: 0)
  • Exomes 𝑓: 1.0 (724721 hom.)
• Consequence: RTTN NM_173630.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.14
• Publications: 11 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• bilateral generalized polymicrogyria

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_173630.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 18-70196614-T-TCTC is Benign according to our data. Variant chr18-70196614-T-TCTC is described in ClinVar as Benign. ClinVar VariationId is 327761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.725_727dupGAG	p.Gly242dup	conservative_inframe_insertion	Exon 7 of 49	NP_775901.3
	RTTN	NM_001318520.2		c.-1829_-1827dupGAG		5_prime_UTR	Exon 7 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.725_727dupGAG	p.Gly242dup	conservative_inframe_insertion	Exon 7 of 49	ENSP00000491507.1	Q86VV8-1
	RTTN	ENST00000581161.5	TSL:1	n.725_727dupGAG		non_coding_transcript_exon	Exon 7 of 48	ENSP00000462926.1	J3KTD2
	RTTN	ENST00000583043.5	TSL:1	n.95_97dupGAG		non_coding_transcript_exon	Exon 2 of 43	ENSP00000462733.1	J3KT00

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145560 AN: 151880 Hom.: 70067 Cov.: 0

Gnomad AFR AF: 0.855

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD2 exomes AF: 0.989 AC: 246318 AN: 248976 AF XY: 0.992

Gnomad AFR exome AF: 0.849

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.996 AC: 1454914 AN: 1461160 Hom.: 724721 Cov.: 35 AF XY: 0.996 AC XY: 724212 AN XY: 726904

African (AFR) AF: 0.854 AC: 28521 AN: 33384

American (AMR) AF: 0.992 AC: 44308 AN: 44648

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26126 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39671 AN: 39672

South Asian (SAS) AF: 1.00 AC: 86145 AN: 86170

European-Finnish (FIN) AF: 1.00 AC: 53413 AN: 53414

Middle Eastern (MID) AF: 0.993 AC: 5721 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1111207 AN: 1111624

Other (OTH) AF: 0.991 AC: 59802 AN: 60358

GnomAD4 genome AF: 0.958 AC: 145669 AN: 151998 Hom.: 70117 Cov.: 0 AF XY: 0.960 AC XY: 71296 AN XY: 74300

African (AFR) AF: 0.855 AC: 35360 AN: 41370

American (AMR) AF: 0.986 AC: 15065 AN: 15278

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3464 AN: 3464

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5166

South Asian (SAS) AF: 0.999 AC: 4809 AN: 4812

European-Finnish (FIN) AF: 1.00 AC: 10588 AN: 10588

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67959 AN: 68002

Other (OTH) AF: 0.974 AC: 2058 AN: 2112

Alfa AF: 0.977 Hom.: 12154

Asia WGS AF: 0.991 AC: 3446 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58913700; hg19: chr18-67863850; COSMIC: COSV55340856;