11-118532377-C-G

Variant names:

• chr11-118532377-C-G
• rs150904224
• NM_032780.4:c.298C>G

Variant summary

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

The NM_032780.4(TMEM25):​c.298C>G​(p.Arg100Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.445
• 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.298C>G	p.Arg100Gly	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.298C>G	p.Arg100Gly	missense_variant	Exon 3 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;.;.;D;.;.;D;D;D;.;D
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M;M;M;.;M;.;.;.;M;M;.
PhyloP100		-0.45
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;D;.;.;D;D;D;.
Vest4		0.66
MutPred		0.57		Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);.;Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);
MVP		0.61
MPC		0.72
ClinPred		0.99	D
GERP RS		0.13
Varity_R		0.47
gMVP		0.64
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150904224; hg19: chr11-118403092;