3-133380151-C-T

Variant names:

• chr3-133380151-C-T
• rs200974256
• NM_023943.4:c.440C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_023943.4(TMEM108):​c.440C>T​(p.Pro147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,613,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P147P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: TMEM108 NM_023943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.404

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01277262).
• BS2: High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM108	NM_023943.4	c.440C>T	p.Pro147Leu	missense_variant	Exon 4 of 6	ENST00000321871.11	NP_076432.1
TMEM108	NM_001136469.3	c.440C>T	p.Pro147Leu	missense_variant	Exon 4 of 6		NP_001129941.1
TMEM108	NM_001282865.2	c.41-10029C>T		intron_variant	Intron 2 of 3		NP_001269794.1
LOC101927432	NR_189054.1	n.131+1512G>A		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM108	ENST00000321871.11	c.440C>T	p.Pro147Leu	missense_variant	Exon 4 of 6	1	NM_023943.4	ENSP00000324651.6

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000823

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000376 AC: 92 AN: 244670 Hom.: 0 AF XY: 0.000367 AC XY: 49 AN XY: 133430

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000758

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000717 AC: 1047 AN: 1460920 Hom.: 0 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 726778

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000882

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74392

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000824

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000617 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000816 AC: 7

ExAC AF: 0.000446 AC: 54

EpiCase AF: 0.000818

EpiControl AF: 0.00131

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440C>T (p.P147L) alteration is located in exon 4 (coding exon 2) of the TMEM108 gene. This alteration results from a C to T substitution at nucleotide position 440, causing the proline (P) at amino acid position 147 to be replaced by a leucine (L). 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	0.078
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.79
DEOGEN2	Benign	0.19	T;T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.73	.;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D;D;N;N;D;N
REVEL	Benign	0.0090
Sift	Benign	0.084	T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;D;T;T;T
Polyphen		0.017	B;B;.;.;B;.
Vest4		0.11
MVP		0.068
MPC		0.20
ClinPred		0.0054	T
GERP RS		0.065
Varity_R		0.054
gMVP		0.071

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

LitVar

Other links and lift over

dbSNP: rs200974256; hg19: chr3-133098995;