3-133380181-C-T

Variant names:

• chr3-133380181-C-T
• rs376720769
• NM_023943.4:c.470C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023943.4(TMEM108):​c.470C>T​(p.Pro157Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. P157H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM108 NM_023943.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.835
• Publications: 4 publications found

Genes affected

TMEM108 (HGNC:28451): (transmembrane protein 108) Predicted to be involved in several processes, including cellular response to brain-derived neurotrophic factor stimulus; nervous system development; and regulation of signal transduction. Predicted to be located in somatodendritic compartment. Predicted to be active in axon; endosome; and postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000300103 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122866035).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023943.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM108	NM_023943.4	MANE Select	c.470C>T	p.Pro157Leu	missense	Exon 4 of 6	NP_076432.1	Q6UXF1-1
	TMEM108	NM_001136469.3		c.470C>T	p.Pro157Leu	missense	Exon 4 of 6	NP_001129941.1	Q6UXF1-1
	TMEM108	NM_001282865.2		c.41-9999C>T		intron	N/A	NP_001269794.1	B3KT64

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM108	ENST00000321871.11	TSL:1 MANE Select	c.470C>T	p.Pro157Leu	missense	Exon 4 of 6	ENSP00000324651.6	Q6UXF1-1
	TMEM108	ENST00000393130.7	TSL:1	c.470C>T	p.Pro157Leu	missense	Exon 4 of 6	ENSP00000376838.3	Q6UXF1-1
	TMEM108	ENST00000515826.1	TSL:1	c.470C>T	p.Pro157Leu	missense	Exon 3 of 4	ENSP00000423338.1	E9PB58

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238132 AF XY: 0.00000769

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459888 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726236

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111064

Other (OTH) AF: 0.0000166 AC: 1 AN: 60254

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.83
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.051
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		0.39	B
Vest4		0.24
MutPred		0.21		Loss of glycosylation at P158 (P = 0.0109)
MVP		0.043
MPC		0.20
ClinPred		0.28	T
GERP RS		3.2
Varity_R		0.077
gMVP		0.10
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs376720769; hg19: chr3-133099025;