Variant 3-50355353-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000266025.4(TMEM115):c.1046C>T(p.Pro349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,492,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TMEM115
ENST00000266025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

Variant links:

Genes affected

TMEM115 (HGNC:30055): (transmembrane protein 115) Enables identical protein binding activity. Involved in retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum. Located in Golgi cisterna membrane and nucleus. Colocalizes with Golgi transport complex. [provided by Alliance of Genome Resources, Apr 2022]

TMEM115 links:

ENSG00000272104 (HGNC:):

ENSG00000272104 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036616653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM115	NM_007024.5 linkuse as main transcript	c.1046C>T	p.Pro349Leu	missense_variant	2/2	ENST00000266025.4	NP_008955.1	Q12893A0A024R2Y2
CYB561D2	NR_111912.2 linkuse as main transcript	n.275+3793G>A		intron_variant
LOC127898564	NR_183066.1 linkuse as main transcript	n.276-2765G>A		intron_variant
LOC127898564	NR_183067.1 linkuse as main transcript	n.389+3307G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM115	ENST00000266025.4 linkuse as main transcript	c.1046C>T	p.Pro349Leu	missense_variant	2/2	1	NM_007024.5	ENSP00000266025.3	Q12893
ENSG00000272104	ENST00000606589.1 linkuse as main transcript	c.127+3793G>A		intron_variant		3		ENSP00000476225.1	U3KQU4
CYB561D2	ENST00000490926.1 linkuse as main transcript	n.365-2765G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000551

AC:

AN:

163468

Hom.:

AF XY:

0.0000805

AC XY:

AN XY:

86922

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000497

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000306

AC:

AN:

1340844

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

658166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000697

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000100

Gnomad4 EAS exome

AF:

0.0000580

Gnomad4 SAS exome

AF:

0.000424

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000476

Gnomad4 OTH exome

AF:

0.0000182

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000340

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1046C>T (p.P349L) alteration is located in exon 2 (coding exon 2) of the TMEM115 gene. This alteration results from a C to T substitution at nucleotide position 1046, causing the proline (P) at amino acid position 349 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

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.067

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.51

M_CAP

Benign

0.0067

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.65

REVEL

Benign

0.23

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.024

Polyphen

0.16

Vest4

0.061

MutPred

0.20

Gain of stability (P = 0.0023);

MVP

0.043

MPC

0.71

ClinPred

0.072

GERP RS

3.2

Varity_R

0.041

gMVP

0.20

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over