16-29963289-G-C

Variant names:

• chr16-29963289-G-C
• rs201972818
• NM_001083613.2:c.146G>C

Variant summary

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

The NM_001083613.2(TMEM219):​c.146G>C​(p.Arg49Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,798 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: TMEM219 NM_001083613.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• 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.146G>C	p.Arg49Pro	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.146G>C	p.Arg49Pro	missense_variant	Exon 2 of 6	1	NM_001083613.2	ENSP00000279396.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249466 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461798 Hom.: 1 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 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: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;T;T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	.;.;T;T;.;.
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.6	M;.;M;.;M;M
PhyloP100		3.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;.;N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.19	T;.;T;.;T;T
Sift4G	Uncertain	0.010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D
Vest4		0.67
MutPred		0.68		Gain of glycosylation at S50 (P = 0.0552);Gain of glycosylation at S50 (P = 0.0552);Gain of glycosylation at S50 (P = 0.0552);Gain of glycosylation at S50 (P = 0.0552);Gain of glycosylation at S50 (P = 0.0552);Gain of glycosylation at S50 (P = 0.0552);
MVP		0.34
MPC		1.0
ClinPred		0.87	D
GERP RS		5.0
PromoterAI		-0.14	Neutral
Varity_R		0.26
gMVP		0.52

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: rs201972818; hg19: chr16-29974610;