2-96254835-G-C

Variant names:

• chr2-96254835-G-C
• rs759138897
• NM_017849.4:c.407C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_017849.4(TMEM127):​c.407C>G​(p.Thr136Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T136M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense, splice_region
• Scores: Splicing: ADA: 0.9397
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.50
• 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_017849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	NM_017849.4	MANE Select	c.407C>G	p.Thr136Arg	missense splice_region	Exon 3 of 4	NP_060319.1
	TMEM127	NM_001193304.3		c.407C>G	p.Thr136Arg	missense splice_region	Exon 3 of 4	NP_001180233.1
	TMEM127	NM_001407282.1		c.155C>G	p.Thr52Arg	missense splice_region	Exon 2 of 3	NP_001394211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.407C>G	p.Thr136Arg	missense splice_region	Exon 3 of 4	ENSP00000258439.3
	TMEM127	ENST00000432959.2	TSL:1	c.407C>G	p.Thr136Arg	missense splice_region	Exon 3 of 4	ENSP00000416660.1
	TMEM127	ENST00000435268.2	TSL:3	c.155C>G	p.Thr52Arg	missense splice_region	Exon 2 of 3	ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.98
MutPred		0.71		Gain of MoRF binding (P = 0.0199)
MVP		0.81
MPC		1.3
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.99
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.60
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: rs759138897; hg19: chr2-96920573;