Genetic Variant TMEM106B:c.*515C>G (chr7-12232490-C-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.*515C>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 0.505 in 151,808 control chromosomes in the GnomAD database, including 20,460 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 0.51 ( 20453 hom., cov: 33)

Exomes 𝑓: 0.32 ( 7 hom. )

Consequence

TMEM106B
NM_001134232.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

13 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=-0.65).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 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.*515C>G		3_prime_UTR	Exon 8 of 8	NP_001127704.1
	TMEM106B	NM_018374.4		c.*515C>G		3_prime_UTR	Exon 9 of 9	NP_060844.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.*515C>G	3_prime_UTR	Exon 8 of 8	ENSP00000379902.3
TMEM106B	ENST00000396667.7	TSL:1	c.*515C>G	3_prime_UTR	Exon 9 of 9	ENSP00000379901.2
TMEM106B	ENST00000444443.6	TSL:4	c.*515C>G	3_prime_UTR	Exon 8 of 8	ENSP00000401302.2

Frequencies

GnomAD3 genomes

AF:

0.505

AC:

76526

AN:

151520

Hom.:

20426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.644

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.529

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.478

GnomAD4 exome

AF:

0.324

AC:

AN:

170

Hom.:

Cov.:

AF XY:

0.277

AC XY:

AN XY:

112

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.311

AC:

AN:

148

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.375

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

76605

AN:

151638

Hom.:

20453

Cov.:

AF XY:

0.507

AC XY:

37553

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.663

AC:

27474

AN:

41434

American (AMR)

AF:

0.543

AC:

8263

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.441

AC:

1529

AN:

3470

East Asian (EAS)

AF:

0.645

AC:

3332

AN:

5164

South Asian (SAS)

AF:

0.613

AC:

2959

AN:

4826

European-Finnish (FIN)

AF:

0.336

AC:

3547

AN:

10552

Middle Eastern (MID)

AF:

0.531

AC:

155

AN:

292

European-Non Finnish (NFE)

AF:

0.413

AC:

27953

AN:

67662

Other (OTH)

AF:

0.478

AC:

1003

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1849

3698

5548

7397

9246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.440

Hom.:

1984

Bravo

AF:

0.527

Asia WGS

AF:

0.594

AC:

2054

AN:

3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over