Genetic Variant TMEM106B:c.282-127T>A (chr7-12224099-T-A) – 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.282-127T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 808,874 control chromosomes in the GnomAD database, including 5,162 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 0.13 ( 1376 hom., cov: 32)

Exomes 𝑓: 0.10 ( 3786 hom. )

Consequence

TMEM106B
NM_001134232.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.06

Publications

4 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=-0.73).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106B	NM_001134232.2 link	c.282-127T>A		intron_variant	Intron 3 of 7	ENST00000396668.8	NP_001127704.1	Q9NUM4A0A024R9Z1
TMEM106B	NM_018374.4 link	c.282-127T>A		intron_variant	Intron 4 of 8		NP_060844.2	Q9NUM4A0A024R9Z1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106B	ENST00000396668.8 link	c.282-127T>A		intron_variant	Intron 3 of 7	1	NM_001134232.2	ENSP00000379902.3		Q9NUM4

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19239

AN:

152100

Hom.:

1374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.0703

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0883

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0956

Gnomad OTH

AF:

0.122

GnomAD4 exome

AF:

0.101

AC:

66390

AN:

656656

Hom.:

3786

AF XY:

0.103

AC XY:

35038

AN XY:

341702

show subpopulations

African (AFR)

AF:

0.193

AC:

3264

AN:

16882

American (AMR)

AF:

0.0933

AC:

2740

AN:

29382

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

1650

AN:

15152

East Asian (EAS)

AF:

0.0713

AC:

2518

AN:

35330

South Asian (SAS)

AF:

0.158

AC:

8026

AN:

50844

European-Finnish (FIN)

AF:

0.111

AC:

5016

AN:

45202

Middle Eastern (MID)

AF:

0.103

AC:

400

AN:

3866

European-Non Finnish (NFE)

AF:

0.0919

AC:

39288

AN:

427316

Other (OTH)

AF:

0.107

AC:

3488

AN:

32682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2869

5738

8608

11477

14346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.126

AC:

19252

AN:

152218

Hom.:

1376

Cov.:

AF XY:

0.126

AC XY:

9374

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.196

AC:

8146

AN:

41518

American (AMR)

AF:

0.101

AC:

1548

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

363

AN:

3472

East Asian (EAS)

AF:

0.0885

AC:

459

AN:

5184

South Asian (SAS)

AF:

0.160

AC:

771

AN:

4824

European-Finnish (FIN)

AF:

0.105

AC:

1110

AN:

10604

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0956

AC:

6500

AN:

67998

Other (OTH)

AF:

0.122

AC:

257

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

845

1690

2534

3379

4224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.108

Hom.:

132

Bravo

AF:

0.126

Asia WGS

AF:

0.114

AC:

397

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.44

(source)

DANN

Benign

0.87

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over