16-29963226-T-A

Variant names:

• chr16-29963226-T-A
• NM_001083613.2:c.83T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083613.2(TMEM219):​c.83T>A​(p.Leu28Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM219 NM_001083613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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	c.83T>A	p.Leu28Gln	missense_variant	Exon 2 of 6	ENST00000279396.11	NP_001077082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM219	ENST00000279396.11	c.83T>A	p.Leu28Gln	missense_variant	Exon 2 of 6	1	NM_001083613.2	ENSP00000279396.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83T>A (p.L28Q) alteration is located in exon 2 (coding exon 1) of the TMEM219 gene. This alteration results from a T to A substitution at nucleotide position 83, causing the leucine (L) at amino acid position 28 to be replaced by a glutamine (Q). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T;T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	.;.;T;T;.;.
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;.;M;.;M;M
PhyloP100		3.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D;.;D;.;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.020	D;.;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D
Vest4		0.66
MutPred		0.45		Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);
MVP		0.39
MPC		0.84
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr16-29974547;