rs772153618

Positions:

• chr2-96254098-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_017849.4(TMEM127):​c.427G>A​(p.Val143Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity TM127_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_017849.4
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM127	NM_017849.4	c.427G>A	p.Val143Ile	missense_variant	4/4	ENST00000258439.8
TMEM127	NM_001193304.3	c.427G>A	p.Val143Ile	missense_variant	4/4
TMEM127	NM_001407282.1	c.175G>A	p.Val59Ile	missense_variant	3/3
TMEM127	NM_001407283.1	c.175G>A	p.Val59Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8	c.427G>A	p.Val143Ile	missense_variant	4/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1	c.427G>A	p.Val143Ile	missense_variant	4/4	1		P1
TMEM127	ENST00000435268.1	c.175G>A	p.Val59Ile	missense_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000239 AC: 6 AN: 251144 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135764

Gnomad AFR exome AF: 0.0000615

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: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

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: 0.0000644 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 21, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 17, 2023

The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000023 (3/128968 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The p.V143I variant (also known as c.427G>A), located in coding exon 3 of the TMEM127 gene, results from a G to A substitution at nucleotide position 427. The valine at codon 143 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 143 of the TMEM127 protein (p.Val143Ile). This variant is present in population databases (rs772153618, gnomAD 0.006%). 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: 463847). 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 tolerated. 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	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.62
MutPred		0.31		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;
MVP		0.69
MPC		0.37
ClinPred		0.26	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs772153618; hg19: chr2-96919836;