7-12214925-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134232.2(TMEM106B):c.115G>C(p.Asp39His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D39V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM106B NM_001134232.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.39

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37392133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM106B	NM_001134232.2	c.115G>C	p.Asp39His	missense_variant	2/8	ENST00000396668.8
TMEM106B	NM_018374.4	c.115G>C	p.Asp39His	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM106B	ENST00000396668.8	c.115G>C	p.Asp39His	missense_variant	2/8	1	NM_001134232.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Vascular dementia Uncertain:1

Uncertain significance, no assertion criteria provided

research

Myllykangas group, University of Helsinki

Apr 01, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.050	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.39
MutPred		0.49		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.14
MPC		0.77
ClinPred		0.91	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.57

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: rs770339502; hg19: chr7-12254551; COSMIC: COSV101188890; COSMIC: COSV101188890;