Genetic Variant TMEM219:p.Ser195Trp (chr16-29968253-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001083613.2(TMEM219):c.584C>G(p.Ser195Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S195L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TMEM219
NM_001083613.2 missense, splice_region

Scores

Splicing: ADA: 0.04353

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.449

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29744047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM219	NM_001083613.2 link	c.584C>G	p.Ser195Trp	missense_variant, splice_region_variant	Exon 4 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.584C>G	p.Ser195Trp	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_001083613.2	ENSP00000279396.6		Q86XT9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458268

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1109070

Other (OTH)

AF:

0.00

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

0.18

BayesDel_addAF

Benign

-0.00089

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;T;T;T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.85

.;T;T;.;.;T

M_CAP

Benign

0.0082

MetaRNN

Benign

0.28

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.90

L;L;.;L;L;.

PhyloP100

0.45

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;D;.;D;D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0090

D;D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

0.97

D;D;.;D;D;.

Vest4

0.53

MutPred

0.35

Gain of catalytic residue at L193 (P = 0.0039);Gain of catalytic residue at L193 (P = 0.0039);Gain of catalytic residue at L193 (P = 0.0039);Gain of catalytic residue at L193 (P = 0.0039);Gain of catalytic residue at L193 (P = 0.0039);.;

MVP

0.32

MPC

0.91

ClinPred

0.92

GERP RS

1.2

Varity_R

0.19

gMVP

0.46

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.044

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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16-29968253-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over