11-118534353-A-G

Variant names:

• chr11-118534353-A-G
• rs12289253
• NM_032780.4:c.1025A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032780.4(TMEM25):​c.1025A>G​(p.Gln342Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,464 control chromosomes in the GnomAD database, including 26,256 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3174 hom., cov: 32)
  • Exomes 𝑓: 0.16 (23082 hom.)
• Consequence: TMEM25 NM_032780.4 missense, splice_region
• Scores: Splicing: ADA: 0.0005554
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 28 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0479385E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4	c.1025A>G	p.Gln342Arg	missense_variant, splice_region_variant	Exon 8 of 9	ENST00000313236.10	NP_116169.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM25	ENST00000313236.10	c.1025A>G	p.Gln342Arg	missense_variant, splice_region_variant	Exon 8 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27663 AN: 151940 Hom.: 3166 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.193 AC: 47991 AN: 248506 AF XY: 0.201

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.0751

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.536

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.159 AC: 232421 AN: 1461406 Hom.: 23082 Cov.: 37 AF XY: 0.165 AC XY: 119644 AN XY: 726976

African (AFR) AF: 0.237 AC: 7935 AN: 33474

American (AMR) AF: 0.0773 AC: 3452 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3948 AN: 26130

East Asian (EAS) AF: 0.474 AC: 18798 AN: 39668

South Asian (SAS) AF: 0.338 AC: 29147 AN: 86194

European-Finnish (FIN) AF: 0.165 AC: 8809 AN: 53366

Middle Eastern (MID) AF: 0.159 AC: 917 AN: 5760

European-Non Finnish (NFE) AF: 0.134 AC: 148470 AN: 1111780

Other (OTH) AF: 0.181 AC: 10945 AN: 60354

GnomAD4 genome AF: 0.182 AC: 27698 AN: 152058 Hom.: 3174 Cov.: 32 AF XY: 0.185 AC XY: 13774 AN XY: 74342

African (AFR) AF: 0.235 AC: 9741 AN: 41478

American (AMR) AF: 0.105 AC: 1610 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3464

East Asian (EAS) AF: 0.524 AC: 2699 AN: 5154

South Asian (SAS) AF: 0.353 AC: 1700 AN: 4812

European-Finnish (FIN) AF: 0.165 AC: 1751 AN: 10590

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9149 AN: 67966

Other (OTH) AF: 0.171 AC: 360 AN: 2110

Alfa AF: 0.153 Hom.: 2373

Bravo AF: 0.177

TwinsUK AF: 0.135 AC: 500

ALSPAC AF: 0.141 AC: 545

ESP6500AA AF: 0.228 AC: 1002

ESP6500EA AF: 0.137 AC: 1174

ExAC AF: 0.196 AC: 23730

EpiCase AF: 0.136

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.70
DEOGEN2	Benign	0.0	.;.;.;.;.;T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.0	.;T;T;T;T;T;T;.
MetaRNN	Benign	0.000087	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	.;.;.;N;.;.;N;.
PhyloP100		0.43
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;N;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Vest4		0.044
ClinPred		0.00041	T
GERP RS		2.1
Varity_R		0.042
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.10		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: rs12289253; hg19: chr11-118405068; COSMIC: COSV107313227; COSMIC: COSV107313227;