chr2-96254107-A-G

Variant names:

• chr2-96254107-A-G
• rs121908827
• NM_017849.4:c.418T>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_017849.4(TMEM127):​c.418T>C​(p.Cys140Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C140Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P: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 Pathogenic. Variant got 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-96254106-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 2-96254107-A-G is Pathogenic according to our data. Variant chr2-96254107-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126970.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-96254107-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.418T>C	p.Cys140Arg	missense_variant	Exon 4 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.418T>C	p.Cys140Arg	missense_variant	Exon 4 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.166T>C	p.Cys56Arg	missense_variant	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.166T>C	p.Cys56Arg	missense_variant	Exon 3 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.418T>C	p.Cys140Arg	missense_variant	Exon 4 of 4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.418T>C	p.Cys140Arg	missense_variant	Exon 4 of 4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.166T>C	p.Cys56Arg	missense_variant	Exon 3 of 3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pheochromocytoma Pathogenic:1

-

Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.80		Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);.;
MVP		0.82
MPC		1.7
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs121908827; hg19: chr2-96919845;