chr17-28357762-G-C

Position:

chr17-28357762-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_152464.3(TMEM199):c.92G>C(p.Arg31Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

TMEM199
NM_152464.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.66

Variant links:

Genes affected

TMEM199 (HGNC:18085): (transmembrane protein 199) The protein encoded by this gene has been observed to localize to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and coat protein complex I (COPI) in some human cells. The encoded protein shares some homology with the yeast protein Vma12. Defects in this gene are a cause of congenital disorder of glycosylation, type IIp. [provided by RefSeq, Mar 2016]

TMEM199 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-28357762-G-C is Pathogenic according to our data. Variant chr17-28357762-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM199	NM_152464.3 linkuse as main transcript	c.92G>C	p.Arg31Pro	missense_variant	1/6	ENST00000292114.8	NP_689677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM199	ENST00000292114.8 linkuse as main transcript	c.92G>C	p.Arg31Pro	missense_variant	1/6	1	NM_152464.3	ENSP00000292114	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

248258

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000542

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461204

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TMEM199-CDG

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 29, 2016

- -

TMEM199-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2023

The TMEM199 c.92G>C variant is predicted to result in the amino acid substitution p.Arg31Pro. This variant has been reported in the homozygous and compound heterozygous states in patients with abnormal protein glycosylation (Jansen et al. 2016. PubMed ID: 26833330; Vajro et al. 2018. PubMed ID: 29321044). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-26684785-G-C). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters TMEM199 gene expression (PMID: 29321044). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 218964). This missense change has been observed in individual(s) with congenital disorder of glycosylation type II (PMID: 26833330, 29321044). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs782531869, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 31 of the TMEM199 protein (p.Arg31Pro). -

Congenital disorders of glycosylation type II

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.088

Eigen

Benign

-0.044

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

REVEL

Benign

0.18

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.62

MutPred

0.33

Loss of MoRF binding (P = 0.0073);

MVP

0.40

MPC

0.96

ClinPred

0.59

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.58

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over