Genetic Variant TMEM128:p.Lys43Asn (chr4-4246312-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001297551.2(TMEM128):c.129A>C(p.Lys43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,610,138 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TMEM128
NM_001297551.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0160

Variant links:

Genes affected

TMEM128 (HGNC:28201): (transmembrane protein 128) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM128 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18512306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM128	NM_001297551.2 link	c.129A>C	p.Lys43Asn	missense_variant	Exon 2 of 5	ENST00000382753.5	NP_001284480.1	Q5BJH2-1B7Z3K1
TMEM128	NM_001297552.2 link	c.129A>C	p.Lys43Asn	missense_variant	Exon 2 of 5		NP_001284481.1	Q5BJH2-1
TMEM128	NM_032927.4 link	c.57A>C	p.Lys19Asn	missense_variant	Exon 2 of 5		NP_116316.1	Q5BJH2-2
TMEM128	XM_005248034.4 link	c.129A>C	p.Lys43Asn	missense_variant	Exon 2 of 5		XP_005248091.1	Q5BJH2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM128	ENST00000382753.5 link	c.129A>C	p.Lys43Asn	missense_variant	Exon 2 of 5	1	NM_001297551.2	ENSP00000372201.4		Q5BJH2-1
TMEM128	ENST00000254742.6 link	c.57A>C	p.Lys19Asn	missense_variant	Exon 2 of 5	1		ENSP00000254742.2		Q5BJH2-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152076

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000607

AC:

AN:

246930

Hom.:

AF XY:

0.0000675

AC XY:

AN XY:

133356

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1458062

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.57A>C (p.K19N) alteration is located in exon 2 (coding exon 2) of the TMEM128 gene. This alteration results from a A to C substitution at nucleotide position 57, causing the lysine (K) at amino acid position 19 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

-0.024

MutationAssessor

Uncertain

2.7

.;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.97

D;P

Vest4

0.36

MutPred

0.30

.;Loss of methylation at K43 (P = 0.0019);

MVP

0.74

MPC

0.47

ClinPred

0.29

GERP RS

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.44

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over