2-96265302-G-T

Variant names:

• chr2-96265302-G-T
• rs983504110
• NM_017849.4:c.80C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017849.4(TMEM127):​c.80C>A​(p.Pro27Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76
• 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: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38003767).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	NM_017849.4	MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 2 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.80C>A	p.Pro27Gln	missense	Exon 2 of 4	NP_001180233.1	O75204
	TMEM127	NM_001407283.1		c.-9+567C>A		intron	N/A	NP_001394212.1	C9J4H2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 2 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.80C>A	p.Pro27Gln	missense	Exon 2 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000910913.1		c.80C>A	p.Pro27Gln	missense	Exon 1 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391688 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687592

African (AFR) AF: 0.00 AC: 0 AN: 31962

American (AMR) AF: 0.00 AC: 0 AN: 36662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36230

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082990

Other (OTH) AF: 0.00 AC: 0 AN: 58064

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.96	D
Vest4		0.45
MutPred		0.18		Loss of loop (P = 9e-04)
MVP		0.81
MPC		0.86
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.64
Mutation Taster		=46/54	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: rs983504110; hg19: chr2-96931040;