Genetic Variant NM_001134232.2:c.442-92A>C (chr7-12229587-A-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.442-92A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 1,039,812 control chromosomes in the GnomAD database, including 3,272 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 0.056 ( 334 hom., cov: 33)

Exomes 𝑓: 0.076 ( 2938 hom. )

Consequence

TMEM106B
NM_001134232.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.345

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:

Genome browser will be placed here

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 (NFE) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106B	NM_001134232.2 link	c.442-92A>C		intron_variant	Intron 4 of 7	ENST00000396668.8	NP_001127704.1	Q9NUM4A0A024R9Z1
TMEM106B	NM_018374.4 link	c.442-92A>C		intron_variant	Intron 5 of 8		NP_060844.2	Q9NUM4A0A024R9Z1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106B	ENST00000396668.8 link	c.442-92A>C		intron_variant	Intron 4 of 7	1	NM_001134232.2	ENSP00000379902.3		Q9NUM4

Frequencies

GnomAD3 genomes

AF:

0.0563

AC:

8565

AN:

152058

Hom.:

334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0841

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.0497

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.0862

Gnomad OTH

AF:

0.0576

GnomAD4 exome

AF:

0.0763

AC:

67698

AN:

887638

Hom.:

2938

AF XY:

0.0752

AC XY:

33320

AN XY:

443128

show subpopulations

African (AFR)

AF:

0.0138

AC:

263

AN:

19064

American (AMR)

AF:

0.0403

AC:

681

AN:

16892

Ashkenazi Jewish (ASJ)

AF:

0.0787

AC:

1217

AN:

15456

East Asian (EAS)

AF:

0.000129

AC:

AN:

30900

South Asian (SAS)

AF:

0.0253

AC:

1096

AN:

43346

European-Finnish (FIN)

AF:

0.0505

AC:

2191

AN:

43362

Middle Eastern (MID)

AF:

0.0878

AC:

237

AN:

2698

European-Non Finnish (NFE)

AF:

0.0874

AC:

59221

AN:

677352

Other (OTH)

AF:

0.0723

AC:

2788

AN:

38568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2941

5882

8824

11765

14706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2014

4028

6042

8056

10070

<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:

0.0563

AC:

8567

AN:

152174

Hom.:

334

Cov.:

AF XY:

0.0554

AC XY:

4123

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0167

AC:

694

AN:

41512

American (AMR)

AF:

0.0524

AC:

800

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0841

AC:

292

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0242

AC:

117

AN:

4826

European-Finnish (FIN)

AF:

0.0497

AC:

527

AN:

10610

Middle Eastern (MID)

AF:

0.110

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0862

AC:

5863

AN:

68000

Other (OTH)

AF:

0.0570

AC:

120

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

412

824

1237

1649

2061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0259

Hom.:

Bravo

AF:

0.0559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.7

(source)

DANN

Benign

0.87

PhyloP100

0.34

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over