Variant 17-43213849-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145041.4(TMEM106A):c.233C>T(p.Ala78Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

TMEM106A
NM_145041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.16

Variant links:

Genes affected

TMEM106A (HGNC:28288): (transmembrane protein 106A) Predicted to be involved in several processes, including glycoprotein biosynthetic process; positive regulation of cytokine production; and positive regulation of intracellular signal transduction. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM106A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM106A	NM_145041.4 linkuse as main transcript	c.233C>T	p.Ala78Val	missense_variant	4/9	ENST00000612339.4	NP_659478.1
TMEM106A	NM_001291586.2 linkuse as main transcript	c.233C>T	p.Ala78Val	missense_variant	4/9		NP_001278515.1
TMEM106A	NM_001291588.2 linkuse as main transcript	c.233C>T	p.Ala78Val	missense_variant	3/7		NP_001278517.1
TMEM106A	NM_001291587.2 linkuse as main transcript	c.89C>T	p.Ala30Val	missense_variant	5/10		NP_001278516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM106A	ENST00000612339.4 linkuse as main transcript	c.233C>T	p.Ala78Val	missense_variant	4/9	2	NM_145041.4	ENSP00000483246	P1	Q96A25-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251462

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135908

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:

0.000817

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727244

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:

0.000788

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000492

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.233C>T (p.A78V) alteration is located in exon 4 (coding exon 2) of the TMEM106A gene. This alteration results from a C to T substitution at nucleotide position 233, causing the alanine (A) at amino acid position 78 to be replaced by a valine (V). 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

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;.;T;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;.;D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.76

D;D;D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.5

.;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.0

.;.;D;D;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;.;D;D

Vest4

0.92, 0.92, 0.91

MutPred

0.81

Gain of ubiquitination at K74 (P = 0.1106);Gain of ubiquitination at K74 (P = 0.1106);.;Gain of ubiquitination at K74 (P = 0.1106);Gain of ubiquitination at K74 (P = 0.1106);

MVP

0.33

ClinPred

0.92

GERP RS

5.7

Varity_R

0.82

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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