chr11-118532194-G-A

Variant names:

• chr11-118532194-G-A
• rs1951314022
• NM_032780.4:c.115G>A

Variant summary

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

The NM_032780.4(TMEM25):​c.115G>A​(p.Glu39Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,450,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• 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.115G>A	p.Glu39Lys	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.115G>A	p.Glu39Lys	missense_variant	Exon 3 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450654 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720420

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.0000452 AC: 2 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 84142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105854

Other (OTH) AF: 0.00 AC: 0 AN: 59898

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>A (p.E39K) alteration is located in exon 3 (coding exon 2) of the TMEM25 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glutamic acid (E) at amino acid position 39 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;.;D;.;T;T;T;.;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	M;M;M;.;M;.;.;M;M;.
PhyloP100		4.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;N;N;D;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T;T;T;D;T;D;T;T;T;T
Sift4G	Benign	0.15	T;T;T;D;T;T;T;T;T;D
Polyphen		0.94	P;P;.;.;D;.;D;D;P;.
Vest4		0.43
MutPred		0.62		Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);
MVP		0.67
MPC		0.24
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.77
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

dbSNP: rs1951314022; hg19: chr11-118402909;