chr11-118533033-G-C

Variant names:

• chr11-118533033-G-C
• rs147483533
• NM_032780.4:c.499G>C

Variant summary

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

The NM_032780.4(TMEM25):​c.499G>C​(p.Asp167His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21
• 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.499G>C	p.Asp167His	missense_variant	Exon 4 of 9	ENST00000313236.10	NP_116169.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM25	ENST00000313236.10	c.499G>C	p.Asp167His	missense_variant	Exon 4 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499G>C (p.D167H) alteration is located in exon 4 (coding exon 3) of the TMEM25 gene. This alteration results from a G to C substitution at nucleotide position 499, causing the aspartic acid (D) at amino acid position 167 to be replaced by a histidine (H). 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	.;.;.;.;.;.;T;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;D;.
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L;L;L;L;.;.;.;L;L
PhyloP100		6.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	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	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;D;D
Vest4		0.50
MutPred		0.71		Loss of catalytic residue at D167 (P = 0.1513);Loss of catalytic residue at D167 (P = 0.1513);Loss of catalytic residue at D167 (P = 0.1513);Loss of catalytic residue at D167 (P = 0.1513);.;.;Loss of catalytic residue at D167 (P = 0.1513);Loss of catalytic residue at D167 (P = 0.1513);Loss of catalytic residue at D167 (P = 0.1513);
MVP		0.43
MPC		0.69
ClinPred		0.98	D
GERP RS		6.0
PromoterAI		-0.021	Neutral
Varity_R		0.54
gMVP		0.64
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 6

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

Other links and lift over

dbSNP: rs147483533; hg19: chr11-118403748;