chr2-96265399-G-A

Variant names:

• chr2-96265399-G-A
• rs121908813
• NM_017849.4:c.-18C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_017849.4(TMEM127):​c.-18C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM127 NM_017849.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.72
• Publications: 1 publications found

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]

TMEM127 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96265399-G-A is Pathogenic according to our data. Variant chr2-96265399-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	NM_017849.4	MANE Select	c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_060319.1	O75204
	TMEM127	NM_017849.4	MANE Select	c.-18C>T		5_prime_UTR	Exon 2 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001180233.1	O75204

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.-18C>T		5_prime_UTR	Exon 2 of 4	ENSP00000258439.3	O75204

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1208598 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 588032

African (AFR) AF: 0.00 AC: 0 AN: 23908

American (AMR) AF: 0.00 AC: 0 AN: 12922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17102

East Asian (EAS) AF: 0.00 AC: 0 AN: 27412

South Asian (SAS) AF: 0.00 AC: 0 AN: 50834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 994768

Other (OTH) AF: 0.00 AC: 0 AN: 49576

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary pheochromocytoma-paraganglioma (1)
1	-	-	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=35/265	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908813; hg19: chr2-96931137;