17-8173448-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_183065.4(TMEM107):c.*755C>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 0.000974 in 762,632 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: TMEM107 NM_183065.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• 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]

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

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 17-8173448-G-A is Benign according to our data. Variant chr17-8173448-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265783.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM107	NM_183065.4	c.*755C>T		3_prime_UTR_variant	5/5	ENST00000437139.7
SNORD118	NR_033294.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM107	ENST00000437139.7	c.*755C>T		3_prime_UTR_variant	5/5	1	NM_183065.4	P1
TMEM107	ENST00000449985.6	c.*804C>T		3_prime_UTR_variant	2/2	1
SNORD118	ENST00000363593.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00113 AC: 261 AN: 231158 Hom.: 2 AF XY: 0.00136 AC XY: 173 AN XY: 127574

Gnomad AFR exome AF: 0.000502

Gnomad AMR exome AF: 0.000265

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000342

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.00107 AC: 652 AN: 610298 Hom.: 7 Cov.: 0 AF XY: 0.00137 AC XY: 456 AN XY: 333564

Gnomad4 AFR exome AF: 0.000283

Gnomad4 AMR exome AF: 0.000345

Gnomad4 ASJ exome AF: 0.0000477

Gnomad4 EAS exome AF: 0.000139

Gnomad4 SAS exome AF: 0.00654

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.000792

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152334 Hom.: 0 Cov.: 34 AF XY: 0.000644 AC XY: 48 AN XY: 74494

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00579

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000856 Hom.: 0

Bravo AF: 0.000382

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leukoencephalopathy with calcifications and cysts Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 10, 2016

- -

Meckel syndrome, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

TMEM107-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.80

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;