Genetic Variant TMEM25:p.Gly146Ser (chr11-118532970-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032780.4(TMEM25):c.436G>A(p.Gly146Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM25
NM_032780.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.22

Publications

0 publications found

Variant links:

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]

TMEM25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4 link	c.436G>A	p.Gly146Ser	missense_variant	Exon 4 of 9	ENST00000313236.10	NP_116169.2	Q86YD3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM25	ENST00000313236.10 link	c.436G>A	p.Gly146Ser	missense_variant	Exon 4 of 9	1	NM_032780.4	ENSP00000315635.5		Q86YD3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250934

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.436G>A (p.G146S) alteration is located in exon 4 (coding exon 3) of the TMEM25 gene. This alteration results from a G to A substitution at nucleotide position 436, causing the glycine (G) at amino acid position 146 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

.;.;.;.;.;.;T;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D;.

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.0

L;L;L;L;.;.;.;L;L

PhyloP100

9.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

N;N;N;N;D;D;N;N;N

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;D;D;D;D

Vest4

0.70

MutPred

0.73

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.33

MPC

0.63

ClinPred

0.82

GERP RS

5.8

PromoterAI

-0.065

Neutral

(source)

Varity_R

0.43

gMVP

0.66

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over