3-50358329-G-C

Position:

chr3-50358329-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007024.5(TMEM115):c.735C>G(p.Ser245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TMEM115
NM_007024.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00600

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:

LOC127898564 (HGNC:):

LOC127898564 links:

CYB561D2 (HGNC:30253): (cytochrome b561 family member D2) Enables heme binding activity and transmembrane monodehydroascorbate reductase activity. Involved in ascorbate homeostasis. Predicted to be located in vesicle. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

CYB561D2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12034914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM115	NM_007024.5 linkuse as main transcript	c.735C>G	p.Ser245Arg	missense_variant	1/2	ENST00000266025.4	NP_008955.1
LOC127898564	NR_183066.1 linkuse as main transcript	n.487G>C		non_coding_transcript_exon_variant	3/5
CYB561D2	NR_111912.2 linkuse as main transcript	n.275+6769G>C		intron_variant, non_coding_transcript_variant
LOC127898564	NR_183067.1 linkuse as main transcript	n.389+6283G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM115	ENST00000266025.4 linkuse as main transcript	c.735C>G	p.Ser245Arg	missense_variant	1/2	1	NM_007024.5	ENSP00000266025	P1
CYB561D2	ENST00000490926.1 linkuse as main transcript	n.576G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251304

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000247

AC:

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

Dec 09, 2023

The c.735C>G (p.S245R) alteration is located in exon 1 (coding exon 1) of the TMEM115 gene. This alteration results from a C to G substitution at nucleotide position 735, causing the serine (S) at amino acid position 245 to be replaced by an arginine (R). 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

0.33

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.078

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.28

M_CAP

Benign

0.0021

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

REVEL

Benign

0.043

Sift

Benign

0.10

Sift4G

Benign

0.34

Polyphen

0.0020

Vest4

0.31

MutPred

0.40

Gain of MoRF binding (P = 0.0111);

MVP

0.082

MPC

0.77

ClinPred

0.051

GERP RS

1.4

Varity_R

0.13

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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