Genetic Variant TMEM106B:p.Asp252Asn (chr7-12231904-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001134232.2(TMEM106B):c.754G>A(p.Asp252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM106B
NM_001134232.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.56

Publications

1 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: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-12231904-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3772686.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 7-12231904-G-A is Pathogenic according to our data. Variant chr7-12231904-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106B	NM_001134232.2 link	c.754G>A	p.Asp252Asn	missense_variant	Exon 8 of 8	ENST00000396668.8	NP_001127704.1
TMEM106B	NM_018374.4 link	c.754G>A	p.Asp252Asn	missense_variant	Exon 9 of 9		NP_060844.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106B	ENST00000396668.8 link	c.754G>A	p.Asp252Asn	missense_variant	Exon 8 of 8	1	NM_001134232.2	ENSP00000379902.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukodystrophy, hypomyelinating, 16

Pathogenic:9

Sep 01, 2022

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

May 01, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

May 08, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.754G>A;p.(Asp252Asn) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 523236; PMID: 29186371; 29194508; 32572497; 32595021) - PS4.The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 29186371; 29444210) - PS2.The variant is located in a mutational hot spot and/or critical and well-established functional domain(DUF1356 domain; PMID:29444210) - PM1. This variant is not present in population databases (rs1554310600, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Likely Pathogenic, for Leukodystrophy, hypomyelinating, 16, autosomal dominant. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29444210). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29444210,29186371).

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM6, PP3, PP5

Jul 14, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar. This variant has also been reported in individuals with TMEM106B-related symptoms (PMID: 29186371, 29444210); This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine; This variant is heterozygous; This gene is associated with autosomal dominant disease; The mechanism of disease for this gene is not clearly established.

not provided

Pathogenic:3

Oct 09, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29186371, 29444210, 32595021, 32543692, 37077564, 32572497, 36950148, 36046422, 33597727)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

3.3

M;M

PhyloP100

9.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.53

Sift

Benign

0.054

T;T

Sift4G

Uncertain

0.022

D;D

Vest4

0.85

ClinPred

1.0

GERP RS

5.4

Varity_R

0.46

gMVP

0.67

Mutation Taster

=2/98

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over