chr2-96254961-C-A

Variant names:

• chr2-96254961-C-A
• rs746831347
• NM_017849.4:c.281G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_017849.4(TMEM127):​c.281G>T​(p.Arg94Leu) variant causes a missense 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. 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. R94W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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_pathogenic. Variant got 8 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-96254962-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.29G>T	p.Arg10Leu	missense_variant	Exon 2 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.29G>T	p.Arg10Leu	missense_variant	Exon 2 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.281G>T	p.Arg94Leu	missense_variant	Exon 3 of 4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.29G>T	p.Arg10Leu	missense_variant	Exon 2 of 3	3		ENSP00000411810.1

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

Jan 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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. This variant has not been reported in the literature in individuals with TMEM127-related conditions. This sequence change replaces arginine with leucine at codon 94 of the TMEM127 protein (p.Arg94Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.031	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.49	P;P;.
Vest4		0.95
MutPred		0.68		Loss of catalytic residue at R94 (P = 0.1483);Loss of catalytic residue at R94 (P = 0.1483);.;
MVP		0.79
MPC		0.65
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.50
gMVP		0.93

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: rs746831347; hg19: chr2-96920699;