chr17-8173448-G-C

Position:

• chr17-8173448-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 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

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]

TMEM107 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-8173448-G-C is Pathogenic according to our data. Variant chr17-8173448-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8173448-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . 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.*755C>G		3_prime_UTR_variant	5/5	ENST00000437139.7	NP_898888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM107	ENST00000437139	c.*755C>G		3_prime_UTR_variant	5/5	1	NM_183065.4	ENSP00000402732.2
TMEM107	ENST00000449985.6	c.*804C>G		3_prime_UTR_variant	2/2	1		ENSP00000404753.2
SNORD118	ENST00000363593.1	n.*6C>G		downstream_gene_variant		6

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

GnomAD3 exomes AF: 0.000614 AC: 142 AN: 231158 Hom.: 0 AF XY: 0.000627 AC XY: 80 AN XY: 127574

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 SAS exome AF: 0.000166

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

Gnomad4 AFR exome AF: 0.000397

Gnomad4 AMR exome AF: 0.000459

Gnomad4 ASJ exome AF: 0.0000477

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.0000795

Gnomad4 NFE exome AF: 0.000834

Gnomad4 OTH exome AF: 0.000640

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

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00142

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

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SNORD118: PM3:Strong, PP1:Strong, PM2, PS3:Supporting -

Leukoencephalopathy with calcifications and cysts Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine

Apr 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.4
DANN	Benign	0.74
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: rs75008470; hg19: chr17-8076766;