chr2-96265261-T-A

Variant names:

• chr2-96265261-T-A
• rs760633411
• NM_017849.4:c.121A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_017849.4(TMEM127):​c.121A>T​(p.Ile41Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,435,170 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I41V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34
• Publications: 0 publications found

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]

TMEM127 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.121A>T	p.Ile41Phe	missense_variant	Exon 2 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.121A>T	p.Ile41Phe	missense_variant	Exon 2 of 4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+608A>T		intron_variant	Intron 1 of 2		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.121A>T	p.Ile41Phe	missense_variant	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1435170 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 10 AN XY: 712814

African (AFR) AF: 0.00 AC: 0 AN: 33150

American (AMR) AF: 0.00 AC: 0 AN: 42242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38728

South Asian (SAS) AF: 0.00 AC: 0 AN: 83574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1103932

Other (OTH) AF: 0.00 AC: 0 AN: 59538

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

Mar 17, 2022

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: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the TMEM127 protein (p.Ile41Phe). This variant is not present in population databases (gnomAD no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		5.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.57		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.79
MPC		1.6
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.90
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs760633411; hg19: chr2-96930999;