Genetic Variant TMEM219:p.Leu25Trp (chr16-29963217-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001083613.2(TMEM219):c.74T>G(p.Leu25Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TMEM219
NM_001083613.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM219	NM_001083613.2 link	c.74T>G	p.Leu25Trp	missense_variant	Exon 2 of 6	ENST00000279396.11	NP_001077082.1	Q86XT9A0A024R618

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM219	ENST00000279396.11 link	c.74T>G	p.Leu25Trp	missense_variant	Exon 2 of 6	1	NM_001083613.2	ENSP00000279396.6		Q86XT9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249374

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135330

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:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727144

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:

0.0000188

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74T>G (p.L25W) alteration is located in exon 2 (coding exon 1) of the TMEM219 gene. This alteration results from a T to G substitution at nucleotide position 74, causing the leucine (L) at amino acid position 25 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

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.24

T;T;T;T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

.;.;T;T;.;.

M_CAP

Benign

0.0063

MetaRNN

Uncertain

0.45

T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.6

M;.;M;.;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.9

D;.;D;.;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

D;.;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.99

D;.;D;.;D;D

Vest4

0.70

MVP

0.36

MPC

1.1

ClinPred

0.94

GERP RS

5.8

Varity_R

0.50

gMVP

0.75

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