NM_017849.4:c.667G>A

Variant names:

• chr2-96253858-C-T
• rs779910556
• NM_017849.4:c.667G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_017849.4(TMEM127):​c.667G>A​(p.Glu223Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E223D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.41
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29006696).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.667G>A	p.Glu223Lys	missense	Exon 4 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.667G>A	p.Glu223Lys	missense	Exon 4 of 4	NP_001180233.1	O75204
	TMEM127	NM_001407282.1		c.415G>A	p.Glu139Lys	missense	Exon 3 of 3	NP_001394211.1	C9J4H2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.667G>A	p.Glu223Lys	missense	Exon 4 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.667G>A	p.Glu223Lys	missense	Exon 4 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000910913.1		c.667G>A	p.Glu223Lys	missense	Exon 3 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461742 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

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: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary pheochromocytoma-paraganglioma (1)
-	1	-	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.036
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.34	N
PhyloP100		7.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T
Sift4G	Uncertain	0.031	D
Polyphen		0.0	B
Vest4		0.28
MutPred		0.19		Gain of ubiquitination at E223 (P = 0.0022)
MVP		0.70
MPC		0.55
ClinPred		0.77	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.48
Mutation Taster		=74/26	polymorphism

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: rs779910556; hg19: chr2-96919596;