Genetic Variant TMEM106B:c.-228T>C (chr7-12211200-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001134232.2(TMEM106B):c.-228T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,314 control chromosomes in the GnomAD database, including 10,419 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 10417 hom., cov: 33)

Exomes 𝑓: 0.13 ( 2 hom. )

Consequence

TMEM106B
NM_001134232.2 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.11

Publications

2 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:

ENSG00000298754 (HGNC:):

ENSG00000298754 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134232.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	NM_001134232.2	MANE Select	c.-228T>C		upstream_gene	N/A	NP_001127704.1
	TMEM106B	NM_018374.4		c.-422T>C		upstream_gene	N/A	NP_060844.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.-228T>C	upstream_gene	N/A	ENSP00000379902.3
TMEM106B	ENST00000396667.7	TSL:1	c.-422T>C	upstream_gene	N/A	ENSP00000379901.2
TMEM106B	ENST00000420833.5	TSL:1	n.-228T>C	upstream_gene	N/A	ENSP00000391016.1

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

49412

AN:

152062

Hom.:

10390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.575

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.419

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.302

GnomAD4 exome

AF:

0.134

AC:

AN:

134

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.134

AC:

AN:

112

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.325

AC:

49497

AN:

152180

Hom.:

10417

Cov.:

AF XY:

0.328

AC XY:

24389

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.575

AC:

23875

AN:

41522

American (AMR)

AF:

0.367

AC:

5615

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

683

AN:

3472

East Asian (EAS)

AF:

0.420

AC:

2157

AN:

5140

South Asian (SAS)

AF:

0.352

AC:

1699

AN:

4830

European-Finnish (FIN)

AF:

0.156

AC:

1652

AN:

10614

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12861

AN:

67984

Other (OTH)

AF:

0.303

AC:

640

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1596

3192

4788

6384

7980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.151

Hom.:

460

Bravo

AF:

0.353

Asia WGS

AF:

0.398

AC:

1380

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.73

(source)

DANN

Benign

0.50

PhyloP100

-2.1

PromoterAI

-0.14

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over