chr11-118532248-G-T

Variant names:

• chr11-118532248-G-T
• NM_032780.4:c.169G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032780.4(TMEM25):​c.169G>T​(p.Gly57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

Genes affected

TMEM25 (HGNC:25890): (transmembrane protein 25) Predicted to be involved in negative regulation of excitatory postsynaptic potential and regulation of protein stability. Predicted to be located in late endosome and lysosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4	c.169G>T	p.Gly57Trp	missense_variant	Exon 3 of 9	ENST00000313236.10	NP_116169.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM25	ENST00000313236.10	c.169G>T	p.Gly57Trp	missense_variant	Exon 3 of 9	1	NM_032780.4	ENSP00000315635.5

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

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>T (p.G57W) alteration is located in exon 3 (coding exon 2) of the TMEM25 gene. This alteration results from a G to T substitution at nucleotide position 169, causing the glycine (G) at amino acid position 57 to be replaced by a tryptophan (W). 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	0.21
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;.;D;.;.;T;D;T;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.79	.;T;T;T;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	0.81	L;L;L;.;L;.;.;.;L;.;L;.
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;N;N;D;D;N;D;N
REVEL	Uncertain	0.49
Sift	Benign	0.20	T;T;T;T;T;D;T;T;T;.;T;T
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;D;.;.;D;D;.;D;.
Vest4		0.36
MutPred		0.66		Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);.;Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);.;Loss of methylation at R53 (P = 0.0339);Loss of methylation at R53 (P = 0.0339);
MVP		0.70
MPC		0.18
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.83
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr11-118402963;