rs1555526172

Variant names:

• chr17-8175980-T-C
• rs1555526172
• NM_183065.4:c.134A>G
• TMEM107 p.Glu45Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3 PP5_Moderate

The NM_183065.4(TMEM107):​c.134A>G​(p.Glu45Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004296738: Experimental studies have shown that this missense change affects TMEM107 function (PMID:26595381).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM107 NM_183065.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.28
• 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):

• ciliopathy

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia
• Meckel syndrome 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004296738: Experimental studies have shown that this missense change affects TMEM107 function (PMID: 26595381).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-8175980-T-C is Pathogenic according to our data. Variant chr17-8175980-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 430703.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM107	NM_183065.4	MANE Select	c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	NP_898888.1	Q6UX40-1
	TMEM107	NM_032354.5		c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	NP_115730.2
	TMEM107	NM_001351278.2		c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	NP_001338207.1	Q6UX40-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM107	ENST00000437139.7	TSL:1 MANE Select	c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	ENSP00000402732.2	Q6UX40-1
	TMEM107	ENST00000316425.9	TSL:1	c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	ENSP00000314116.5	Q6UX40-4
	TMEM107	ENST00000533070.5	TSL:1	c.134A>G	p.Glu45Gly	missense	Exon 2 of 5	ENSP00000436674.1	Q6UX40-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Leukoencephalopathy with calcifications and cysts (1)
1	-	-	not provided (1)
1	-	-	Orofaciodigital syndrome 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
PromoterAI		-0.077	Neutral
Varity_R		0.40
gMVP		0.70
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 0
DS_DL_spliceai		0.52		Position offset: -21

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555526172;

hg19: chr17-8079298;

COSMIC: COSV108145458;

COSMIC: COSV108145458;