17-8173448-G-C

Variant names:

• chr17-8173448-G-C
• rs75008470
• NM_183065.4:c.*755C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_183065.4(TMEM107):​c.*755C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000624 in 762,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: TMEM107 NM_183065.4 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.80
• Publications: 3 publications found

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)

SNORD118 Gene-Disease associations (from GenCC):

• leukoencephalopathy with calcifications and cysts

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 17-8173448-G-C is Pathogenic according to our data. Variant chr17-8173448-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 929264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183065.4. 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
	TMEM107	NM_183065.4	MANE Select	c.*755C>G		3_prime_UTR	Exon 5 of 5	NP_898888.1
	TMEM107	NR_147092.2		n.1006C>G		non_coding_transcript_exon	Exon 2 of 2
	TMEM107	NM_032354.5		c.*755C>G		3_prime_UTR	Exon 5 of 5	NP_115730.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM107	ENST00000437139.7	TSL:1 MANE Select	c.*755C>G		3_prime_UTR	Exon 5 of 5	ENSP00000402732.2
	TMEM107	ENST00000449985.6	TSL:1	c.*804C>G		3_prime_UTR	Exon 2 of 2	ENSP00000404753.2
	SNORD118	ENST00000363593.2	TSL:6 MANE Select	n.*4C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000614 AC: 142 AN: 231158 AF XY: 0.000627

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000323

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000512

GnomAD4 exome AF: 0.000605 AC: 369 AN: 610300 Hom.: 1 Cov.: 0 AF XY: 0.000564 AC XY: 188 AN XY: 333566

African (AFR) AF: 0.000397 AC: 7 AN: 17638

American (AMR) AF: 0.000459 AC: 20 AN: 43528

Ashkenazi Jewish (ASJ) AF: 0.0000477 AC: 1 AN: 20954

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 36008

South Asian (SAS) AF: 0.000302 AC: 21 AN: 69546

European-Finnish (FIN) AF: 0.0000795 AC: 3 AN: 37734

Middle Eastern (MID) AF: 0.00126 AC: 4 AN: 3178

European-Non Finnish (NFE) AF: 0.000834 AC: 291 AN: 348896

Other (OTH) AF: 0.000640 AC: 21 AN: 32818

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152334 Hom.: 0 Cov.: 34 AF XY: 0.000644 AC XY: 48 AN XY: 74494

African (AFR) AF: 0.000289 AC: 12 AN: 41576

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000752

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SNORD118: PM3:Strong, PP1:Strong, PM2, PS3:Supporting

Nov 20, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the homozygous state, or along with a second SNORD118 variant, in multiple unrelated patients with clinical features of SNORD118-related cerebral microangiopathy in the published literature and referred for genetic testing at GeneDx (PMID: 32361877, 27571260, 32359472, 3261877, 27571260); Published functional studies demonstrate a damaging effect with this nucleotide alteration disrupting the processing of the precursor U8 RNA (PMID: 27571260); Changes the Watson-Crick match to a mismatch at a position where a Watson-Crick match is moderately conserved across species, which is predicted to affect the secondary structure/function; Located in a stem of the SNORD118 non-coding RNA (PMID: 32359472); This variant is associated with the following publications: (PMID: 34426522, 32361877, 27571260, 33029936, 32359472)

Leukoencephalopathy with calcifications and cysts Pathogenic:1

Apr 06, 2020

Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.4
DANN	Benign	0.74
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=97/3	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs75008470; hg19: chr17-8076766;