3-133380129-A-C

Variant names:

• chr3-133380129-A-C
• NM_023943.4:c.418A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023943.4(TMEM108):​c.418A>C​(p.Thr140Pro) 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. 12/21 in silico tools predict 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: 1.92

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=0.33246827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM108	NM_023943.4	c.418A>C	p.Thr140Pro	missense_variant	Exon 4 of 6	ENST00000321871.11	NP_076432.1
TMEM108	NM_001136469.3	c.418A>C	p.Thr140Pro	missense_variant	Exon 4 of 6		NP_001129941.1
TMEM108	NM_001282865.2	c.41-10051A>C		intron_variant	Intron 2 of 3		NP_001269794.1
LOC101927432	NR_189054.1	n.131+1534T>G		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM108	ENST00000321871.11	c.418A>C	p.Thr140Pro	missense_variant	Exon 4 of 6	1	NM_023943.4	ENSP00000324651.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418A>C (p.T140P) alteration is located in exon 4 (coding exon 2) of the TMEM108 gene. This alteration results from a A to C substitution at nucleotide position 418, causing the threonine (T) at amino acid position 140 to be replaced by a proline (P). 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	Benign	0.084
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.62	.;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.0	L;L;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;D;D;D;N;D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;T;D;D;T
Polyphen		1.0	D;D;.;.;D;.
Vest4		0.42
MutPred		0.42		Gain of catalytic residue at P139 (P = 0.0112);Gain of catalytic residue at P139 (P = 0.0112);.;Gain of catalytic residue at P139 (P = 0.0112);Gain of catalytic residue at P139 (P = 0.0112);Gain of catalytic residue at P139 (P = 0.0112);
MVP		0.13
MPC		0.86
ClinPred		0.86	D
GERP RS		3.7
Varity_R		0.42
gMVP		0.23

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: chr3-133098973;