2-96254035-A-C

Position:

• chr2-96254035-A-C

Variant summary

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

The NM_017849.4(TMEM127):​c.490T>G​(p.Tyr164Asp) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

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 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.490T>G	p.Tyr164Asp	missense_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.490T>G	p.Tyr164Asp	missense_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.238T>G	p.Tyr80Asp	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.238T>G	p.Tyr80Asp	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.490T>G	p.Tyr164Asp	missense_variant	4/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.490T>G	p.Tyr164Asp	missense_variant	4/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.238T>G	p.Tyr80Asp	missense_variant	3/3	3		ENSP00000411810

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 cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2024

The p.Y164D variant (also known as c.490T>G), located in coding exon 3 of the TMEM127 gene, results from a T to G substitution at nucleotide position 490. The tyrosine at codon 164 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.033	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.62
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;
MVP		0.88
MPC		1.1
ClinPred		0.89	D
GERP RS		6.1
Varity_R		0.42
gMVP		0.88

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: chr2-96919773;