rs121908825

Variant summary

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

The NM_017849.4(TMEM127):​c.409+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM127
NM_017849.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.49
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.22873083 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 7, new splice context is: gccGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-96254832-C-A is Pathogenic according to our data. Variant chr2-96254832-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM127NM_017849.4 linkuse as main transcriptc.409+1G>T splice_donor_variant, intron_variant ENST00000258439.8 NP_060319.1 O75204
TMEM127NM_001193304.3 linkuse as main transcriptc.409+1G>T splice_donor_variant, intron_variant NP_001180233.1 O75204
TMEM127NM_001407282.1 linkuse as main transcriptc.157+1G>T splice_donor_variant, intron_variant NP_001394211.1
TMEM127NM_001407283.1 linkuse as main transcriptc.157+1G>T splice_donor_variant, intron_variant NP_001394212.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM127ENST00000258439.8 linkuse as main transcriptc.409+1G>T splice_donor_variant, intron_variant 1 NM_017849.4 ENSP00000258439.3 O75204
TMEM127ENST00000432959.1 linkuse as main transcriptc.409+1G>T splice_donor_variant, intron_variant 1 ENSP00000416660.1 O75204
TMEM127ENST00000435268.1 linkuse as main transcriptc.157+1G>T splice_donor_variant, intron_variant 3 ENSP00000411810.1 C9J4H2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJan 27, 2022- -
Likely pathogenic, no assertion criteria providedliterature onlyFamilial Cancer Clinic, Veneto Institute of Oncology-- -
Likely pathogenic, no assertion criteria providedresearchdeCODE genetics, AmgenJul 21, 2023The variant NM_017849.4:c.409+1G>T (chr2:96254832) in TMEM127 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 01, 2019The c.409+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the TMEM127 gene. This mutation was identified in a 38 year-old Spanish woman with a benign adrenal pheochromocytoma/paraganglioma whose tumor demonstrated loss of heterozygosity (LOH) of the wild-type allele. Subsequent RNA analysis confirmed that this alteration results in in-frame skipping of exon 3 (coding exon 2), which is a large percentage of the protein (Yao L et al. JAMA, 2010 Dec;304:2611-9). This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.75
Position offset: 2
DS_DL_spliceai
1.0
Position offset: 1

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.

Other links and lift over

dbSNP: rs121908825; hg19: chr2-96920570; API