3-133379928-C-T

Variant names:

• chr3-133379928-C-T
• rs202042493
• NM_023943.4:c.217C>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.217C>T​(p.Pro73Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P73T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TMEM108 NM_023943.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 0 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=0.16279736).

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.217C>T	p.Pro73Ser	missense	Exon 4 of 6	NP_076432.1	Q6UXF1-1
	TMEM108	NM_001136469.3		c.217C>T	p.Pro73Ser	missense	Exon 4 of 6	NP_001129941.1	Q6UXF1-1
	TMEM108	NM_001282865.2		c.41-10252C>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.217C>T	p.Pro73Ser	missense	Exon 4 of 6	ENSP00000324651.6	Q6UXF1-1
	TMEM108	ENST00000393130.7	TSL:1	c.217C>T	p.Pro73Ser	missense	Exon 4 of 6	ENSP00000376838.3	Q6UXF1-1
	TMEM108	ENST00000515826.1	TSL:1	c.217C>T	p.Pro73Ser	missense	Exon 3 of 4	ENSP00000423338.1	E9PB58

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74172

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	0.069
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Benign	0.041	D
Sift4G	Benign	0.29	T
Polyphen		0.98	D
Vest4		0.084
MutPred		0.30		Loss of catalytic residue at P73 (P = 0.0017)
MVP		0.20
MPC		0.23
ClinPred		0.65	D
GERP RS		3.8
Varity_R		0.063
gMVP		0.20
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202042493; hg19: chr3-133098772;