Genetic Variant TMEM115:p.Ala76Val (chr3-50358837-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007024.5(TMEM115):c.227C>T(p.Ala76Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM115
NM_007024.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.16168895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM115	NM_007024.5 link	c.227C>T	p.Ala76Val	missense_variant	Exon 1 of 2	ENST00000266025.4	NP_008955.1	Q12893A0A024R2Y2
LOC127898564	NR_111912.2 link	n.275+7277G>A		intron_variant	Intron 2 of 3
LOC127898564	NR_183066.1 link	n.834+161G>A		intron_variant	Intron 3 of 4
LOC127898564	NR_183067.1 link	n.389+6791G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM115	ENST00000266025.4 link	c.227C>T	p.Ala76Val	missense_variant	Exon 1 of 2	1	NM_007024.5	ENSP00000266025.3		Q12893
ENSG00000272104	ENST00000606589.1 link	c.127+7277G>A		intron_variant	Intron 2 of 3	3		ENSP00000476225.1		U3KQU4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250330

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460898

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.227C>T (p.A76V) alteration is located in exon 1 (coding exon 1) of the TMEM115 gene. This alteration results from a C to T substitution at nucleotide position 227, causing the alanine (A) at amino acid position 76 to be replaced by a valine (V). 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

0.073

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.041

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Benign

0.0088

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

3.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.18

REVEL

Benign

0.17

Sift

Benign

0.73

Sift4G

Benign

0.71

Polyphen

0.058

Vest4

0.33

MutPred

0.52

Gain of sheet (P = 0.0028);

MVP

0.12

MPC

0.67

ClinPred

0.50

GERP RS

4.4

Varity_R

0.12

gMVP

0.73

Mutation Taster

=49/51

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over