chr7-12229791-C-T

Position:

• chr7-12229791-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001134232.2(TMEM106B):​c.554C>T​(p.Thr185Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TMEM106B NM_001134232.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM106B	NM_001134232.2	c.554C>T	p.Thr185Ile	missense_variant	5/8	ENST00000396668.8
TMEM106B	NM_018374.4	c.554C>T	p.Thr185Ile	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM106B	ENST00000396668.8	c.554C>T	p.Thr185Ile	missense_variant	5/8	1	NM_001134232.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.021	T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.000081	P;P
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.16
Sift	Benign	0.60	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.63	P;P
Vest4		0.81
MutPred		0.48		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.13
MPC		0.28
ClinPred		0.92	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-12269417;