11-118532274-G-T

Variant names:

• chr11-118532274-G-T
• rs782689375
• NM_032780.4:c.195G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032780.4(TMEM25):​c.195G>T​(p.Trp65Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4	c.195G>T	p.Trp65Cys	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.195G>T	p.Trp65Cys	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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;.;.;D;.;.;D;D;D;.;.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D;D;T;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	M;M;M;.;M;.;.;.;M;.;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;T;D;D
Polyphen		1.0	D;D;.;.;D;.;.;D;D;.;D;.
Vest4		0.92
MutPred		0.83		Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);.;Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);.;Gain of methylation at R62 (P = 0.0395);Gain of methylation at R62 (P = 0.0395);
MVP		0.85
MPC		0.80
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.98
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs782689375; hg19: chr11-118402989;