2-96254107-A-C

Position:

• chr2-96254107-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The ENST00000258439.8(TMEM127):​c.418T>G​(p.Cys140Gly) 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. 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. C140R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 ENST00000258439.8 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity TM127_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000258439.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.418T>G	p.Cys140Gly	missense_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.418T>G	p.Cys140Gly	missense_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.166T>G	p.Cys56Gly	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.166T>G	p.Cys56Gly	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.418T>G	p.Cys140Gly	missense_variant	4/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.418T>G	p.Cys140Gly	missense_variant	4/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.166T>G	p.Cys56Gly	missense_variant	3/3	3		ENSP00000411810

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.70		Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);.;
MVP		0.83
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr2-96919845;