3-133379770-C-A

Variant names:

• chr3-133379770-C-A
• NM_023943.4:c.59C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023943.4(TMEM108):​c.59C>A​(p.Ala20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM108 NM_023943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38207868).

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.59C>A	p.Ala20Glu	missense	Exon 4 of 6	NP_076432.1	Q6UXF1-1
	TMEM108	NM_001136469.3		c.59C>A	p.Ala20Glu	missense	Exon 4 of 6	NP_001129941.1	Q6UXF1-1
	TMEM108	NM_001282865.2		c.41-10410C>A		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.59C>A	p.Ala20Glu	missense	Exon 4 of 6	ENSP00000324651.6	Q6UXF1-1
	TMEM108	ENST00000393130.7	TSL:1	c.59C>A	p.Ala20Glu	missense	Exon 4 of 6	ENSP00000376838.3	Q6UXF1-1
	TMEM108	ENST00000515826.1	TSL:1	c.59C>A	p.Ala20Glu	missense	Exon 3 of 4	ENSP00000423338.1	E9PB58

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.074	T
Polyphen		0.98	D
Vest4		0.60
MutPred		0.62		Gain of relative solvent accessibility (P = 0.09)
MVP		0.22
MPC		0.48
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.34
gMVP		0.74
Mutation Taster		=77/23	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

hg19: chr3-133098614;