NM_001083613.2:c.583T>A

Variant names:

• chr16-29968252-T-A
• rs781591004
• NM_001083613.2:c.583T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083613.2(TMEM219):​c.583T>A​(p.Ser195Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S195L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TMEM219 NM_001083613.2 missense, splice_region
• Scores: Splicing: ADA: 0.01071
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10289088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM219	NM_001083613.2	c.583T>A	p.Ser195Thr	missense_variant, splice_region_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.583T>A	p.Ser195Thr	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_001083613.2	ENSP00000279396.6

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248874 AF XY: 0.00000740

Gnomad AFR exome AF: 0.000194

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: 0.00000411 AC: 6 AN: 1458850 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725080

African (AFR) AF: 0.000150 AC: 5 AN: 33420

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109566

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.000169 AC: 7 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583T>A (p.S195T) alteration is located in exon 4 (coding exon 3) of the TMEM219 gene. This alteration results from a T to A substitution at nucleotide position 583, causing the serine (S) at amino acid position 195 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	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T;T;T;T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.64	.;T;T;.;.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.095	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.;L;L;.
PhyloP100		1.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N;.;N;N;.
REVEL	Benign	0.094
Sift	Benign	0.15	T;T;.;T;T;.
Sift4G	Benign	0.063	T;T;T;T;T;D
Polyphen		0.13	B;B;.;B;B;.
Vest4		0.30
MutPred		0.24		Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);.;
MVP		0.085
MPC		0.37
ClinPred		0.038	T
GERP RS		3.3
Varity_R		0.059
gMVP		0.22
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.21
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

Other links and lift over

dbSNP: rs781591004; hg19: chr16-29979573;