7-12229791-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001134232.2(TMEM106B):c.554C>G(p.Thr185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,603,674 control chromosomes in the GnomAD database, including 167,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.50 ( 20500 hom., cov: 33)

Exomes 𝑓: 0.44 ( 146861 hom. )

Consequence

TMEM106B
NM_001134232.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.98

Publications

144 publications found

Variant links:

Genes affected

TMEM106B (HGNC:22407): (transmembrane protein 106B) Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

TMEM106B Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 16
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TMEM106B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.123355E-5).

BP6

Variant 7-12229791-C-G is Benign according to our data. Variant chr7-12229791-C-G is described in ClinVar as Benign. ClinVar VariationId is 1168238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106B	NM_001134232.2 link	c.554C>G	p.Thr185Ser	missense_variant	Exon 5 of 8	ENST00000396668.8	NP_001127704.1
TMEM106B	NM_018374.4 link	c.554C>G	p.Thr185Ser	missense_variant	Exon 6 of 9		NP_060844.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106B	ENST00000396668.8 link	c.554C>G	p.Thr185Ser	missense_variant	Exon 5 of 8	1	NM_001134232.2	ENSP00000379902.3

Frequencies

GnomAD3 genomes

AF:

0.505

AC:

76690

AN:

151952

Hom.:

20473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.429

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.440

Gnomad EAS

AF:

0.643

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.477

GnomAD2 exomes

AF:

0.491

AC:

120502

AN:

245634

AF XY:

0.488

show subpopulations

Gnomad AFR exome

AF:

0.672

Gnomad AMR exome

AF:

0.590

Gnomad ASJ exome

AF:

0.436

Gnomad EAS exome

AF:

0.658

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.411

Gnomad OTH exome

AF:

0.457

GnomAD4 exome

AF:

0.441

AC:

640722

AN:

1451604

Hom.:

146861

Cov.:

AF XY:

0.444

AC XY:

320863

AN XY:

722152

show subpopulations

African (AFR)

AF:

0.673

AC:

22232

AN:

33044

American (AMR)

AF:

0.583

AC:

25130

AN:

43092

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

11307

AN:

25916

East Asian (EAS)

AF:

0.624

AC:

24679

AN:

39564

South Asian (SAS)

AF:

0.615

AC:

52085

AN:

84724

European-Finnish (FIN)

AF:

0.340

AC:

18146

AN:

53362

Middle Eastern (MID)

AF:

0.477

AC:

2721

AN:

5700

European-Non Finnish (NFE)

AF:

0.413

AC:

456782

AN:

1106200

Other (OTH)

AF:

0.461

AC:

27640

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

15806

31611

47417

63222

79028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14340

28680

43020

57360

71700

<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:

0.505

AC:

76769

AN:

152070

Hom.:

20500

Cov.:

AF XY:

0.507

AC XY:

37668

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.664

AC:

27537

AN:

41488

American (AMR)

AF:

0.542

AC:

8286

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.440

AC:

1525

AN:

3466

East Asian (EAS)

AF:

0.644

AC:

3329

AN:

5170

South Asian (SAS)

AF:

0.613

AC:

2953

AN:

4814

European-Finnish (FIN)

AF:

0.333

AC:

3522

AN:

10570

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.413

AC:

28064

AN:

67966

Other (OTH)

AF:

0.476

AC:

1007

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1883

3766

5649

7532

9415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.415

Hom.:

9729

Bravo

AF:

0.527

TwinsUK

AF:

0.416

AC:

1542

ALSPAC

AF:

0.427

AC:

1646

ESP6500AA

AF:

0.658

AC:

2897

ESP6500EA

AF:

0.417

AC:

3587

ExAC

AF:

0.490

AC:

59520

Asia WGS

AF:

0.594

AC:

2065

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.420

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leukodystrophy, hypomyelinating, 16

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.44

.;T

MetaRNN

Benign

0.000031

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

L;L

PhyloP100

6.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.027

Sift

Benign

0.21

T;T

Sift4G

Benign

0.67

T;T

Polyphen

0.043

B;B

Vest4

0.14

MutPred

0.17

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MPC

0.24

ClinPred

0.017

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.47

Mutation Taster

=85/15

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over