Genetic Variant TMEM127:c.*3025G>C (chr2-96250783-C-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017849.4(TMEM127):c.*3025G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 232,722 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 (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.107

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

TMEM127 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000286 (23/80494) while in subpopulation MID AF = 0.00813 (4/492). AF 95% confidence interval is 0.00278. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 16 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	Effect	Exon Rank	Protein	UniProt
TMEM127	NM_017849.4	MANE Select	c.*3025G>C	3_prime_UTR	Exon 4 of 4	NP_060319.1	O75204
TMEM127	NM_001193304.3		c.*3025G>C	3_prime_UTR	Exon 4 of 4	NP_001180233.1	O75204
TMEM127	NM_001407282.1		c.*3025G>C	3_prime_UTR	Exon 3 of 3	NP_001394211.1	C9J4H2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.*3025G>C	3_prime_UTR	Exon 4 of 4	ENSP00000258439.3	O75204
TMEM127	ENST00000432959.2	TSL:1	c.*3025G>C	3_prime_UTR	Exon 4 of 4	ENSP00000416660.1	O75204
TMEM127	ENST00000910913.1		c.*3025G>C	3_prime_UTR	Exon 3 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000286

AC:

AN:

80494

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

37026

show subpopulations

African (AFR)

AF:

0.000259

AC:

AN:

3866

American (AMR)

AF:

0.00

AC:

AN:

2484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5100

East Asian (EAS)

AF:

0.00

AC:

AN:

11350

South Asian (SAS)

AF:

0.00

AC:

AN:

696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00813

AC:

AN:

492

European-Non Finnish (NFE)

AF:

0.000302

AC:

AN:

49720

Other (OTH)

AF:

0.000446

AC:

AN:

6724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000105

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41534

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68010

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000106

Hom.:

Bravo

AF:

0.000102

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

(source)

DANN

Benign

0.56

PhyloP100

0.11

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over