chr2-96253905-G-A

Position:

• chr2-96253905-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP3 BP4 BS2

The NM_017849.4(TMEM127):​c.620C>T​(p.Ala207Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,700 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A207A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.39

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_benign. Variant got -2 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
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, phyloP100way_vertebrate, PrimateAI [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.41925257).
• BS2: High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.620C>T	p.Ala207Val	missense_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.620C>T	p.Ala207Val	missense_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.368C>T	p.Ala123Val	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.368C>T	p.Ala123Val	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.620C>T	p.Ala207Val	missense_variant	4/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.620C>T	p.Ala207Val	missense_variant	4/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.368C>T	p.Ala123Val	missense_variant	3/3	3		ENSP00000411810

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251414 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TMEM127-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

The TMEM127 c.620C>T variant is predicted to result in the amino acid substitution p.Ala207Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as uncertain by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/405198/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The p.A207V variant (also known as c.620C>T), located in coding exon 3 of the TMEM127 gene, results from a C to T substitution at nucleotide position 620. The alanine at codon 207 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 207 of the TMEM127 protein (p.Ala207Val). This variant is present in population databases (rs751044006, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 405198). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.068	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Uncertain	0.49
Sift	Benign	0.050	D;D;T
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.69	P;P;.
Vest4		0.56
MutPred		0.29		Loss of glycosylation at S212 (P = 0.2361);Loss of glycosylation at S212 (P = 0.2361);.;
MVP		0.76
MPC		1.2
ClinPred		0.62	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751044006; hg19: chr2-96919643; COSMIC: COSV51497658;