17-8174241-AT-A

Variant names:

• chr17-8174241-AT-A
• rs1555525895
• NM_183065.4:c.384delA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000437139.7(TMEM107):​c.384delA​(p.Leu128PhefsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM107 ENST00000437139.7 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.965
• Publications: 0 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]

TMEM107 Gene-Disease associations (from GenCC):

• Meckel syndrome 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome 16

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000266824 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0922 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-8174241-AT-A is Pathogenic according to our data. Variant chr17-8174241-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 430704.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000437139.7. 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.384delA	p.Leu128PhefsTer8	frameshift	Exon 5 of 5	NP_898888.1
	TMEM107	NM_032354.5		c.402delA	p.Leu134PhefsTer8	frameshift	Exon 5 of 5	NP_115730.2
	TMEM107	NM_001351278.2		c.381delA	p.Leu127PhefsTer8	frameshift	Exon 5 of 5	NP_001338207.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM107	ENST00000437139.7	TSL:1 MANE Select	c.384delA	p.Leu128PhefsTer8	frameshift	Exon 5 of 5	ENSP00000402732.2
	TMEM107	ENST00000316425.9	TSL:1	c.402delA	p.Leu134PhefsTer8	frameshift	Exon 5 of 5	ENSP00000314116.5
	TMEM107	ENST00000533070.5	TSL:1	c.381delA	p.Leu127PhefsTer8	frameshift	Exon 5 of 5	ENSP00000436674.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Meckel syndrome 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555525895; hg19: chr17-8077559;