Variant rs1215337884 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_017849.4(TMEM127):c.570delC(p.Thr191fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.70

Variant links:

Genes affected

TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]

TMEM127 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 0.205 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 2-96253954-TG-T is Pathogenic according to our data. Variant chr2-96253954-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-96253954-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4 linkuse as main transcript	c.570delC	p.Thr191fs	frameshift_variant	4/4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_001193304.3 linkuse as main transcript	c.570delC	p.Thr191fs	frameshift_variant	4/4		NP_001180233.1	O75204
TMEM127	NM_001407282.1 linkuse as main transcript	c.318delC	p.Thr107fs	frameshift_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1 linkuse as main transcript	c.318delC	p.Thr107fs	frameshift_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.570delC	p.Thr191fs	frameshift_variant	4/4	1	NM_017849.4	ENSP00000258439.3	O75204
TMEM127	ENST00000432959.1 linkuse as main transcript	c.570delC	p.Thr191fs	frameshift_variant	4/4	1		ENSP00000416660.1	O75204
TMEM127	ENST00000435268.1 linkuse as main transcript	c.318delC	p.Thr107fs	frameshift_variant	3/3	3		ENSP00000411810.1	C9J4H2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251452

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2023

Frameshift variant expected to result in the last 48 amino acids being replaced with 115 different amino acids, and other truncating variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28567294) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2023

The c.570delC variant, located in coding exon 3 of the TMEM127 gene, results from a deletion of one nucleotide at nucleotide position 570, causing a translational frameshift with a predicted alternate stop codon (p.T191Rfs*116). This alteration occurs at the 3' terminus of the TMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 67 amino acids. This frameshift impacts the last 48 amino acids of the native protein. However, frameshifts are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TMEM127-related disease (Ambry internal data; Yu R et al. Endocrinol Diabetes Metab Case Rep 2017 May;2017). An alteration resulting in the same elongation (c.572delC; p.T191RFS*116) was identified in an individual with bilateral pheochromocytoma (Patócs A et al. Pathol. Oncol. Res., 2016 Oct;22:673-9). Other similar frameshifting elongations have been identified in individuals diagnosed with pheochromocytomas (Armaiz-Pena G et al. J Clin Endocrinol Metab 2021 Jan;106(1):e350-e364). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2019

This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Met214Serfs98*) have been observed in individuals with TMEM127-related conditions (PMID: 21156949). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The¬†p.Thr191Argfs*116 variant has been observed in individuals with pheochromocytoma (PMID: 26960314,28567294, Invitae). ClinVar contains an entry for this variant (Variation ID: 486549). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the TMEM127 gene (p.Thr191Argfs*116). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the TMEM127 protein and extend the protein by an additional 67 amino acids. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over