rs750870974

Positions:

• chr2-96254848-C-A
• chr2-96254848-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_017849.4(TMEM127):​c.394G>T​(p.Ala132Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A132T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_017849.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM127	NM_017849.4	c.394G>T	p.Ala132Ser	missense_variant	3/4	ENST00000258439.8
TMEM127	NM_001193304.3	c.394G>T	p.Ala132Ser	missense_variant	3/4
TMEM127	NM_001407282.1	c.142G>T	p.Ala48Ser	missense_variant	2/3
TMEM127	NM_001407283.1	c.142G>T	p.Ala48Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8	c.394G>T	p.Ala132Ser	missense_variant	3/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1	c.394G>T	p.Ala132Ser	missense_variant	3/4	1		P1
TMEM127	ENST00000435268.1	c.142G>T	p.Ala48Ser	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2023

This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 2130969). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 132 of the TMEM127 protein (p.Ala132Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.
Eigen	Benign	0.047
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.86	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.30	B;B;.
Vest4		0.75
MutPred		0.36		Gain of MoRF binding (P = 0.2532);Gain of MoRF binding (P = 0.2532);.;
MVP		0.53
MPC		0.94
ClinPred		0.87	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96920586;