Variant 11-60922113-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000227525.8(TMEM109):c.680G>A(p.Arg227His) variant causes a missense change. The variant allele was found at a frequency of 0.0000831 in 1,612,022 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 (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

TMEM109
ENST00000227525.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Variant links:

Genes affected

TMEM109 (HGNC:28771): (transmembrane protein 109) Predicted to enable voltage-gated ion channel activity. Acts upstream of or within cellular response to gamma radiation and negative regulation of cell death. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM109 links:

ENSG00000256196 (HGNC:):

ENSG00000256196 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=0.2134046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM109	NM_024092.3 linkuse as main transcript	c.680G>A	p.Arg227His	missense_variant	4/4	ENST00000227525.8	NP_076997.1	Q9BVC6
LOC124902676	XR_007062688.1 linkuse as main transcript	n.180-2960C>T		intron_variant
LOC124902676	XR_007062689.1 linkuse as main transcript	n.103+2181C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM109	ENST00000227525.8 linkuse as main transcript	c.680G>A	p.Arg227His	missense_variant	4/4	1	NM_024092.3	ENSP00000227525.3	Q9BVC6
TMEM109	ENST00000536171.1 linkuse as main transcript	c.680G>A	p.Arg227His	missense_variant	3/3	2		ENSP00000443990.1	Q9BVC6
ENSG00000256196	ENST00000543907.2 linkuse as main transcript	n.180-2960C>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000453

AC:

AN:

242584

Hom.:

AF XY:

0.0000453

AC XY:

AN XY:

132554

show subpopulations

Gnomad AFR exome

AF:

0.0000679

Gnomad AMR exome

AF:

0.00

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:

0.0000831

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000808

AC:

118

AN:

1459796

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

726210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000104

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000827

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

Jan 06, 2023

The c.680G>A (p.R227H) alteration is located in exon 4 (coding exon 3) of the TMEM109 gene. This alteration results from a G to A substitution at nucleotide position 680, causing the arginine (R) at amino acid position 227 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.0021

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

0.68

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.24

B;B

Vest4

0.33

MVP

0.34

MPC

1.1

ClinPred

0.15

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.38

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