Genetic Variant TMEM127:p.Ser30Gly (chr2-96265294-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_017849.4(TMEM127):c.88A>G(p.Ser30Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00032 in 1,552,786 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S30R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 4.33

Publications

0 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TMEM127 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_017849.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40699703).

BP6

Variant 2-96265294-T-C is Benign according to our data. Variant chr2-96265294-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 405201.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000344 (482/1400576) while in subpopulation NFE AF = 0.000434 (472/1087624). AF 95% confidence interval is 0.000401. There are 0 homozygotes in GnomAdExome4. There are 220 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

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.88A>G	p.Ser30Gly	missense	Exon 2 of 4	NP_060319.1	O75204
TMEM127	NM_001193304.3		c.88A>G	p.Ser30Gly	missense	Exon 2 of 4	NP_001180233.1	O75204
TMEM127	NM_001407283.1		c.-9+575A>G		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.88A>G	p.Ser30Gly	missense	Exon 2 of 4	ENSP00000258439.3	O75204
TMEM127	ENST00000432959.2	TSL:1	c.88A>G	p.Ser30Gly	missense	Exon 2 of 4	ENSP00000416660.1	O75204
TMEM127	ENST00000910913.1		c.88A>G	p.Ser30Gly	missense	Exon 1 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000599

AC:

AN:

150266

AF XY:

0.0000726

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000344

AC:

482

AN:

1400576

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

220

AN XY:

692898

show subpopulations

African (AFR)

AF:

0.0000929

AC:

AN:

32286

American (AMR)

AF:

0.00

AC:

AN:

37640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

36702

South Asian (SAS)

AF:

0.00

AC:

AN:

80618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

0.000434

AC:

472

AN:

1087624

Other (OTH)

AF:

0.000120

AC:

AN:

58440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.0000985

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000718

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Hereditary pheochromocytoma and paraganglioma (1)

Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.41

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.7

PhyloP100

4.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.48

Sift

Benign

0.034

Sift4G

Benign

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.83

Mutation Taster

=56/44

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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TMEM127 p.Ser30Gly

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over