7-12231904-G-A

Position:

• chr7-12231904-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM106B NM_001134232.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 523236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-12231904-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-12231904-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM106B	NM_001134232.2	c.754G>A	p.Asp252Asn	missense_variant	8/8	ENST00000396668.8	NP_001127704.1
TMEM106B	NM_018374.4	c.754G>A	p.Asp252Asn	missense_variant	9/9		NP_060844.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM106B	ENST00000396668.8	c.754G>A	p.Asp252Asn	missense_variant	8/8	1	NM_001134232.2	ENSP00000379902	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukodystrophy, hypomyelinating, 16 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 08, 2018	- -
Pathogenic, criteria provided, single submitter	research	MyeliNeuroGene Lab, McGill University Health Center Research Institute	Sep 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PM6, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 01, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2023	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.53
Sift	Benign	0.054	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.93		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);
MVP		0.55
MPC		0.87
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs1554310600; hg19: chr7-12271530; COSMIC: COSV67543986; COSMIC: COSV67543986;