rs756818796

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_017849.4(TMEM127):​c.619G>A​(p.Ala207Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,856 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A207A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a chain Transmembrane protein 127 (size 237) in uniprot entity TM127_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_017849.4
BP4
Computational evidence support a benign effect (MetaRNN=0.34549987).
BS2
High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM127NM_017849.4 linkuse as main transcriptc.619G>A p.Ala207Thr missense_variant 4/4 ENST00000258439.8 NP_060319.1
TMEM127NM_001193304.3 linkuse as main transcriptc.619G>A p.Ala207Thr missense_variant 4/4 NP_001180233.1
TMEM127NM_001407282.1 linkuse as main transcriptc.367G>A p.Ala123Thr missense_variant 3/3 NP_001394211.1
TMEM127NM_001407283.1 linkuse as main transcriptc.367G>A p.Ala123Thr missense_variant 3/3 NP_001394212.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM127ENST00000258439.8 linkuse as main transcriptc.619G>A p.Ala207Thr missense_variant 4/41 NM_017849.4 ENSP00000258439 P1
TMEM127ENST00000432959.1 linkuse as main transcriptc.619G>A p.Ala207Thr missense_variant 4/41 ENSP00000416660 P1
TMEM127ENST00000435268.1 linkuse as main transcriptc.367G>A p.Ala123Thr missense_variant 3/33 ENSP00000411810

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251426
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461708
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000225
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000974
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 04, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 05, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 20, 2023The p.A207T variant (also known as c.619G>A), located in coding exon 3 of the TMEM127 gene, results from a G to A substitution at nucleotide position 619. The alanine at codon 207 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary pheochromocytoma-paraganglioma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2023This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 207 of the TMEM127 protein (p.Ala207Thr). This variant is present in population databases (rs756818796, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 241227). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.021
T;T;.
Eigen
Benign
-0.012
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
.;D;D
M_CAP
Uncertain
0.092
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
0.55
N;N;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-0.83
N;N;N
REVEL
Uncertain
0.40
Sift
Benign
0.072
T;T;T
Sift4G
Uncertain
0.026
D;D;D
Polyphen
0.0030
B;B;.
Vest4
0.56
MutPred
0.28
Gain of glycosylation at A207 (P = 0.0227);Gain of glycosylation at A207 (P = 0.0227);.;
MVP
0.71
MPC
1.2
ClinPred
0.69
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.72

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.

Other links and lift over

dbSNP: rs756818796; hg19: chr2-96919644; API