rs201787275

Positions:

• chr17-8173444-G-A
• chr17-8173444-G-C
• chr17-8173444-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_183065.4(TMEM107):​c.*759C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 761,870 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: TMEM107 NM_183065.4 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.65

Genes affected

TMEM107 (HGNC:28128): (transmembrane protein 107) This gene encodes a transmembrane protein and component of the primary cilia transition zone. The encoded protein regulates ciliogenesis and ciliary protein composition. Human fibroblasts expressing a mutant allele of this gene exhibit reduced numbers of cilia, altered cilia length, and impaired sonic hedgehog signaling. In human patients, different mutations in this gene cause different ciliopathies, including Meckel-Gruber syndrome and orofaciodigital syndrome. [provided by RefSeq, May 2017]

SNORD118 (HGNC:32952): (small nucleolar RNA, C/D box 118)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 17-8173444-G-A is Pathogenic according to our data. Variant chr17-8173444-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8173444-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM107	NM_183065.4	c.*759C>T		3_prime_UTR_variant	5/5	ENST00000437139.7	NP_898888.1
SNORD118	NR_033294.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM107	ENST00000437139.7	c.*759C>T		3_prime_UTR_variant	5/5	1	NM_183065.4	ENSP00000402732	P1
TMEM107	ENST00000449985.6	c.*808C>T		3_prime_UTR_variant	2/2	1		ENSP00000404753
SNORD118	ENST00000363593.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00196 AC: 454 AN: 231218 Hom.: 2 AF XY: 0.00201 AC XY: 256 AN XY: 127578

Gnomad AFR exome AF: 0.000790

Gnomad AMR exome AF: 0.000822

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000285

Gnomad SAS exome AF: 0.00169

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.00206 AC: 1254 AN: 609592 Hom.: 3 Cov.: 0 AF XY: 0.00204 AC XY: 680 AN XY: 333104

Gnomad4 AFR exome AF: 0.000851

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000955

Gnomad4 EAS exome AF: 0.000167

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.000239

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74466

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000468 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy with calcifications and cysts Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine	Apr 06, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 25, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jan 03, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SNORD118: PM3:Strong, PM2:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2024	Functional studies provide conflicting evidence, with one study suggesting this variant alters processing of the precursor U8 snoRNAs while another study suggests this variant is functional (PMID: 27571260, 32359472); Variant in a snoRNA that alters a C:G Watson-Crick base pair to a U:G wobble base pair in the 3' extension (PMID: 32359472); This variant is associated with the following publications: (PMID: 32359472, 33029936, 27571260, 34426522, 37761957, 36697224, 34937159, 34986804, 34220662, 32400930, 34380746, 31521395, 32358219, 31912665) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201787275; hg19: chr17-8076762;