11-118532242-G-C

Variant names:

• chr11-118532242-G-C
• rs781968336
• NM_032780.4:c.163G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032780.4(TMEM25):​c.163G>C​(p.Ala55Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TMEM25 NM_032780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.981
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16708907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM25	NM_032780.4	c.163G>C	p.Ala55Pro	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.163G>C	p.Ala55Pro	missense_variant	Exon 3 of 9	1	NM_032780.4	ENSP00000315635.5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249990 AF XY: 0.0000222

Gnomad AFR exome AF: 0.0000619

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: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461162 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111570

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163G>C (p.A55P) alteration is located in exon 3 (coding exon 2) of the TMEM25 gene. This alteration results from a G to C substitution at nucleotide position 163, causing the alanine (A) at amino acid position 55 to be replaced by a proline (P). 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	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;.;.;T;.;T;T;T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	.;T;T;T;T;T;T;T;.;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;L;L;.;L;.;.;L;L;.
PhyloP100		0.98
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;.;B;.;B;B;B;.
Vest4		0.24
MutPred		0.67		Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);Gain of disorder (P = 0.0728);
MVP		0.36
MPC		0.42
ClinPred		0.072	T
GERP RS		0.84
Varity_R		0.20
gMVP		0.64
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs781968336; hg19: chr11-118402957;