rs148567547

Positions:

chr4-183691323-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021942.6(TRAPPC11):c.1901A>G(p.Asn634Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000513 in 1,515,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

TRAPPC11
NM_021942.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.10

Variant links:

Genes affected

TRAPPC11 (HGNC:25751): (trafficking protein particle complex subunit 11) The protein encoded by this gene is a subunit of the TRAPP (transport protein particle) tethering complex, which functions in intracellular vesicle trafficking. This subunit is involved in early stage endoplasmic reticulum-to-Golgi vesicle transport. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2013]

TRAPPC11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2743297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC11	NM_021942.6 linkuse as main transcript	c.1901A>G	p.Asn634Ser	missense_variant	19/30	ENST00000334690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC11	ENST00000334690.11 linkuse as main transcript	c.1901A>G	p.Asn634Ser	missense_variant	19/30	1	NM_021942.6	P1	Q7Z392-1
TRAPPC11	ENST00000357207.8 linkuse as main transcript	c.1901A>G	p.Asn634Ser	missense_variant	19/31	1			Q7Z392-3
TRAPPC11	ENST00000512476.1 linkuse as main transcript	c.719A>G	p.Asn240Ser	missense_variant	8/19	1
TRAPPC11	ENST00000505676.5 linkuse as main transcript	c.*15A>G		3_prime_UTR_variant, NMD_transcript_variant	7/19	1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

232168

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

125600

show subpopulations

Gnomad AFR exome

AF:

0.0000664

Gnomad AMR exome

AF:

0.0000662

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000280

Gnomad OTH exome

AF:

0.000360

GnomAD4 exome

AF:

0.000542

AC:

739

AN:

1363022

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

350

AN XY:

672972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.0000495

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000183

Gnomad4 NFE exome

AF:

0.000677

Gnomad4 OTH exome

AF:

0.000252

GnomAD4 genome

AF:

0.000250

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31597922, 28404951, 27270441) -

Autosomal recessive limb-girdle muscular dystrophy type R18

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 634 of the TRAPPC11 protein (p.Asn634Ser). This variant is present in population databases (rs148567547, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TRAPPC11-related conditions. ClinVar contains an entry for this variant (Variation ID: 448694). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRAPPC11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1901A>G (p.N634S) alteration is located in exon 19 (coding exon 18) of the TRAPPC11 gene. This alteration results from a A to G substitution at nucleotide position 1901, causing the asparagine (N) at amino acid position 634 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0076

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.1

N;N;D

REVEL

Uncertain

0.48

Sift

Benign

0.032

D;D;D

Sift4G

Benign

0.16

T;T;D

Polyphen

0.96

D;P;D

Vest4

0.74

MVP

0.52

MPC

0.40

ClinPred

0.14

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.56

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

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