16-29968171-G-A

Variant names:

• chr16-29968171-G-A
• rs200066942
• NM_001083613.2:c.502G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001083613.2(TMEM219):​c.502G>A​(p.Ala168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TMEM219 NM_001083613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047826022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM219	NM_001083613.2	c.502G>A	p.Ala168Thr	missense_variant	Exon 4 of 6	ENST00000279396.11	NP_001077082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM219	ENST00000279396.11	c.502G>A	p.Ala168Thr	missense_variant	Exon 4 of 6	1	NM_001083613.2	ENSP00000279396.6

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000369 AC: 92 AN: 249576 AF XY: 0.000273

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000794

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000259 AC XY: 188 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1112010

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74340

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.000562 AC: 68

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.502G>A (p.A168T) alteration is located in exon 4 (coding exon 3) of the TMEM219 gene. This alteration results from a G to A substitution at nucleotide position 502, causing the alanine (A) at amino acid position 168 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T;T;T;T;.
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	.;T;T;.;.;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	L;L;.;L;L;.
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N;N;.;N;N;.
REVEL	Benign	0.030
Sift	Benign	0.052	T;T;.;T;T;.
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.18	B;B;.;B;B;.
Vest4		0.11
MVP		0.17
MPC		0.22
ClinPred		0.055	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.27
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200066942; hg19: chr16-29979492;