rs189327749

Positions:

• chr2-96254826-G-A
• chr2-96254826-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017849.4(TMEM127):​c.409+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,613,922 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (35 hom.)
• Consequence: TMEM127 NM_017849.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003331
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.64

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-96254826-G-A is Benign according to our data. Variant chr2-96254826-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-96254826-G-A is described in Lovd as [Likely_benign]. Variant chr2-96254826-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (706/152238) while in subpopulation NFE AF= 0.0064 (435/68000). AF 95% confidence interval is 0.0059. There are 1 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 706 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.409+7C>T		splice_region_variant, intron_variant		ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.409+7C>T		splice_region_variant, intron_variant			NP_001180233.1
TMEM127	NM_001407282.1	c.157+7C>T		splice_region_variant, intron_variant			NP_001394211.1
TMEM127	NM_001407283.1	c.157+7C>T		splice_region_variant, intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.409+7C>T		splice_region_variant, intron_variant		1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.409+7C>T		splice_region_variant, intron_variant		1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.157+7C>T		splice_region_variant, intron_variant		3		ENSP00000411810.1

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 705 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00640

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00494 AC: 1241 AN: 251378 Hom.: 3 AF XY: 0.00515 AC XY: 700 AN XY: 135868

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00595 AC: 8698 AN: 1461684 Hom.: 35 Cov.: 32 AF XY: 0.00578 AC XY: 4204 AN XY: 727136

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00901

Gnomad4 NFE exome AF: 0.00688

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.00464 AC: 706 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74428

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00640

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00524 Hom.: 3

Bravo AF: 0.00406

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2020	Variant summary: TMEM127 c.409+7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0049 in 251378 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is significantly higher than the estimated maximal expected allele frequency for a pathogenic variant in TMEM127 causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (3.1e-07), strongly suggesting that the variant is benign. c.409+7C>T has been reported in the literature in sequencing studies of individuals affected with Paraganglioma and/or Pheochromocytoma (example Abermil_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TMEM127: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pheochromocytoma Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 26, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary pheochromocytoma-paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.55
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.010
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: rs189327749; hg19: chr2-96920564; COSMIC: COSV99302629;