Genetic Variant TMEM127:p.Met1? (chr2-96265379-C-T) – ACMG Classification: Pathogenic (24 pts)

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1PS1_ModeratePS3PM2PP5_Very_Strong

The NM_017849.4(TMEM127):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000021 in 1,426,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000760916: Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID:21156949).".

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.07

Publications

1 publications found

Variant links:

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

TMEM127 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 24 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 53 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 96254989. Lost 0.353 part of the original CDS.

PS1

Another start lost variant in NM_017849.4 (TMEM127) was described as [Pathogenic] in ClinVar

PS3

PS3 evidence extracted from ClinVar submissions: SCV000760916: Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID: 21156949).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-96265379-C-T is Pathogenic according to our data. Variant chr2-96265379-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 532514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM127	NM_017849.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 4	NP_060319.1	O75204
TMEM127	NM_001193304.3		c.3G>A	p.Met1?	start_lost	Exon 2 of 4	NP_001180233.1	O75204
TMEM127	NM_001407283.1		c.-9+490G>A		intron	N/A	NP_001394212.1	C9J4H2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 4	ENSP00000258439.3	O75204
TMEM127	ENST00000432959.2	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 4	ENSP00000416660.1	O75204
TMEM127	ENST00000910913.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000157

AC:

AN:

1274416

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

624168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25366

American (AMR)

AF:

0.00

AC:

AN:

20642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19176

East Asian (EAS)

AF:

0.00

AC:

AN:

29680

South Asian (SAS)

AF:

0.00

AC:

AN:

63436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3664

European-Non Finnish (NFE)

AF:

0.00000194

AC:

AN:

1028928

Other (OTH)

AF:

0.00

AC:

AN:

52674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Hereditary pheochromocytoma and paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.43

PhyloP100

4.1

PROVEAN

Benign

-0.91

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0020

Vest4

0.94

MutPred

0.94

Loss of MoRF binding (P = 0.0982)

MVP

0.80

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.73

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over