Genetic Variant TMEM106B:p.Thr185Asn (chr7-12229791-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001134232.2(TMEM106B):c.554C>A(p.Thr185Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000755 in 1,456,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

TMEM106B
NM_001134232.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.98

Publications

144 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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

BS2

High AC in GnomAdExome4 at 11 AD gene.

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.554C>A	p.Thr185Asn	missense	Exon 5 of 8	NP_001127704.1
	TMEM106B	NM_018374.4		c.554C>A	p.Thr185Asn	missense	Exon 6 of 9	NP_060844.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.554C>A	p.Thr185Asn	missense	Exon 5 of 8	ENSP00000379902.3
TMEM106B	ENST00000396667.7	TSL:1	c.554C>A	p.Thr185Asn	missense	Exon 6 of 9	ENSP00000379901.2
TMEM106B	ENST00000420833.5	TSL:1	n.*440C>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000391016.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456116

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33138

American (AMR)

AF:

0.00

AC:

AN:

43166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

84880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000991

AC:

AN:

1110152

Other (OTH)

AF:

0.00

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

9729

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.7

PhyloP100

6.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.13

Sift

Benign

0.039

Sift4G

Benign

0.35

Polyphen

0.77

Vest4

0.75

MutPred

0.37

Loss of sheet (P = 0.0457)

MVP

0.10

MPC

0.65

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.38

gMVP

0.69

Mutation Taster

=47/53

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over