chr11-118533001-G-T

Variant names:

• chr11-118533001-G-T
• rs113919895
• NM_032780.4:c.467G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032780.4(TMEM25):​c.467G>T​(p.Arg156Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,614,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05
• Publications: 1 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17766923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4	c.467G>T	p.Arg156Leu	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.467G>T	p.Arg156Leu	missense_variant	Exon 4 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251248 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00

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: 0.0000150 AC: 22 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

African (AFR) AF: 0.000508 AC: 17 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74518

African (AFR) AF: 0.000481 AC: 20 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467G>T (p.R156L) alteration is located in exon 4 (coding exon 3) of the TMEM25 gene. This alteration results from a G to T substitution at nucleotide position 467, causing the arginine (R) at amino acid position 156 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;.;.;.;.;.;T;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;L;L;L;.;.;.;L;L
PhyloP100		6.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;D;D
Vest4		0.71
MutPred		0.72		Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);.;.;Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);
MVP		0.25
MPC		0.20
ClinPred		0.31	T
GERP RS		6.0
PromoterAI		-0.0098	Neutral
Varity_R		0.38
gMVP		0.65
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs113919895; hg19: chr11-118403716;