2-96254889-G-C

Variant names:

• chr2-96254889-G-C
• NM_017849.4:c.353C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_017849.4(TMEM127):​c.353C>G​(p.Pro118Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.50

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 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.101C>G	p.Pro34Arg	missense_variant	Exon 2 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.101C>G	p.Pro34Arg	missense_variant	Exon 2 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.353C>G	p.Pro118Arg	missense_variant	Exon 3 of 4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.101C>G	p.Pro34Arg	missense_variant	Exon 2 of 3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.29	T;T;T
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.94	P;P;.
Vest4		0.98
MutPred		0.60		Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);.;
MVP		0.78
MPC		1.3
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96920627;