Genetic Variant TMEM106B:c.*1551A>G (chr7-12233526-A-G) – 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.*1551A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 150,740 control chromosomes in the GnomAD database, including 10,707 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 0.37 ( 10706 hom., cov: 29)

Exomes 𝑓: 0.75 ( 1 hom. )

Consequence

TMEM106B
NM_001134232.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.93

Publications

17 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:

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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=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106B	NM_001134232.2 link	c.*1551A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000396668.8	NP_001127704.1
TMEM106B	NM_018374.4 link	c.*1551A>G		3_prime_UTR_variant	Exon 9 of 9		NP_060844.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
TMEM106B	ENST00000396668.8 link	c.*1551A>G	3_prime_UTR_variant	Exon 8 of 8	1	NM_001134232.2	ENSP00000379902.3
TMEM106B	ENST00000396667.7 link	c.*1551A>G	3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000379901.2
TMEM106B	ENST00000444443.6 link	c.*1551A>G	3_prime_UTR_variant	Exon 8 of 8	4		ENSP00000401302.2
TMEM106B	ENST00000704417.1 link	c.*1551A>G	3_prime_UTR_variant	Exon 8 of 8			ENSP00000515893.1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

55759

AN:

150622

Hom.:

10690

Cov.:

show subpopulations

Gnomad AFR

AF:

0.445

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.430

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.440

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.355

GnomAD4 exome

AF:

0.750

AC:

AN:

Hom.:

Cov.:

AF XY:

0.750

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.370

AC:

55816

AN:

150736

Hom.:

10706

Cov.:

AF XY:

0.373

AC XY:

27425

AN XY:

73620

show subpopulations

African (AFR)

AF:

0.445

AC:

18352

AN:

41226

American (AMR)

AF:

0.430

AC:

6506

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1116

AN:

3458

East Asian (EAS)

AF:

0.532

AC:

2735

AN:

5144

South Asian (SAS)

AF:

0.439

AC:

2108

AN:

4800

European-Finnish (FIN)

AF:

0.249

AC:

2563

AN:

10306

Middle Eastern (MID)

AF:

0.377

AC:

110

AN:

292

European-Non Finnish (NFE)

AF:

0.316

AC:

21264

AN:

67388

Other (OTH)

AF:

0.355

AC:

745

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1722

3445

5167

6890

8612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.343

Hom.:

18483

Bravo

AF:

0.388

Asia WGS

AF:

0.453

AC:

1572

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.35

(source)

DANN

Benign

0.79

PhyloP100

-2.9

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over