rs201263451

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021942.6(TRAPPC11):c.1277T>C(p.Val426Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000787 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

TRAPPC11
NM_021942.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.00

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17247248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC11	NM_021942.6 linkuse as main transcript	c.1277T>C	p.Val426Ala	missense_variant	12/30	ENST00000334690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC11	ENST00000334690.11 linkuse as main transcript	c.1277T>C	p.Val426Ala	missense_variant	12/30	1	NM_021942.6	P1	Q7Z392-1
TRAPPC11	ENST00000357207.8 linkuse as main transcript	c.1277T>C	p.Val426Ala	missense_variant	12/31	1			Q7Z392-3
TRAPPC11	ENST00000512476.1 linkuse as main transcript	c.95T>C	p.Val32Ala	missense_variant	1/19	1
TRAPPC11	ENST00000505676.5 linkuse as main transcript	c.348+38T>C		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251384

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000868

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:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461534

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type R18

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 10, 2022	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 426 of the TRAPPC11 protein (p.Val426Ala). This variant is present in population databases (rs201263451, gnomAD 0.02%). 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: 574490). 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 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 18, 2022	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.047

T;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.10

T;T;D

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0040

B;B;B

Vest4

0.38

MVP

0.44

MPC

0.66

ClinPred

0.062

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.69

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