3-133379770-C-A

Position:

• chr3-133379770-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

LOC101927432 (HGNC:):

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=0.38207868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM108	NM_023943.4	c.59C>A	p.Ala20Glu	missense_variant	4/6	ENST00000321871.11	NP_076432.1
LOC101927432	XR_007096099.1	n.5957+1893G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM108	ENST00000321871.11	c.59C>A	p.Ala20Glu	missense_variant	4/6	1	NM_023943.4	ENSP00000324651	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.59C>A (p.A20E) alteration is located in exon 4 (coding exon 2) of the TMEM108 gene. This alteration results from a C to A substitution at nucleotide position 59, causing the alanine (A) at amino acid position 20 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	.;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.97	L;L;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N;N;D;D;N;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Benign	0.074	T;T;D;D;D;D
Polyphen		0.98	D;D;.;.;D;.
Vest4		0.60
MutPred		0.62		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);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

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: chr3-133098614;