Variant 16-29971513-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001083613.2(TMEM219):c.691C>T(p.Arg231Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,599,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMEM219
NM_001083613.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.825

Variant links:

Genes affected

TMEM219 (HGNC:25201): (transmembrane protein 219) Predicted to be involved in apoptotic process. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM219 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=0.063946694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM219	NM_001083613.2 linkuse as main transcript	c.691C>T	p.Arg231Trp	missense_variant	5/6	ENST00000279396.11	NP_001077082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM219	ENST00000279396.11 linkuse as main transcript	c.691C>T	p.Arg231Trp	missense_variant	5/6	1	NM_001083613.2	ENSP00000279396	P1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249466

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135336

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 SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1448700

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

720778

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:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000725

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150806

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73578

show subpopulations

Gnomad4 AFR

AF:

0.0000244

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Aug 16, 2022

The c.691C>T (p.R231W) alteration is located in exon 5 (coding exon 4) of the TMEM219 gene. This alteration results from a C to T substitution at nucleotide position 691, causing the arginine (R) at amino acid position 231 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;T;T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.76

.;T;.;.

M_CAP

Benign

0.0026

MetaRNN

Benign

0.064

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.17

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.051

T;T;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.35

MutPred

0.26

Loss of disorder (P = 0.0162);Loss of disorder (P = 0.0162);Loss of disorder (P = 0.0162);Loss of disorder (P = 0.0162);

MVP

0.23

MPC

0.24

ClinPred

0.75

GERP RS

3.4

Varity_R

0.054

gMVP

0.27

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