rs397509418

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_021942.6(TRAPPC11):c.1287+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TRAPPC11
NM_021942.6 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.70

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type R18
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Orphanet
intellectual disability-hyperkinetic movement-truncal ataxia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
triple-A syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRAPPC11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-183684059-G-A is Pathogenic according to our data. Variant chr4-183684059-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC11	NM_021942.6 link	c.1287+5G>A		splice_region_variant, intron_variant	Intron 12 of 29	ENST00000334690.11	NP_068761.4	Q7Z392-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRAPPC11	ENST00000334690.11 link	c.1287+5G>A	splice_region_variant, intron_variant	Intron 12 of 29	1	NM_021942.6	ENSP00000335371.6	Q7Z392-1
TRAPPC11	ENST00000357207.8 link	c.1287+5G>A	splice_region_variant, intron_variant	Intron 12 of 30	1		ENSP00000349738.4	Q7Z392-3
TRAPPC11	ENST00000512476.1 link	c.105+5G>A	splice_region_variant, intron_variant	Intron 1 of 18	1		ENSP00000421004.1	D6RHE5
TRAPPC11	ENST00000505676.5 link	n.348+53G>A	intron_variant	Intron 5 of 18	1		ENSP00000422915.1	D6R9T9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251300

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461082

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111380

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000601

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type R18

Pathogenic:7

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 11, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 02, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Intron variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23830518). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.65). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23830518). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000060511 /PMID: 23830518). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 01, 2017

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant previously described as pathogenic and as a founder mutation was identified in homozygous tate in a patient with strabismus, mildly elevated CK, moderate ID, movement disorder. Both parent were heterozygous carriers. -

Dec 07, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 12 of the TRAPPC11 gene. It does not directly change the encoded amino acid sequence of the TRAPPC11 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs397509418, gnomAD 0.009%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and/or movement disorder and intellectual disability (PMID: 23830518, 29158550). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 11-12, but is expected to preserve the integrity of the reading-frame (PMID: 23830518). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:5

Feb 07, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate disruption of the Golgi apparatus architecture and impaired the binding ability of TRAPPC11 to TRAPPC2 (Bogershausen et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 26322222, 24843229, 23830518, 29158550, 31575891, 32528171, 34426522, 25697177) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal recessive 23

Pathogenic:1

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The c.1287+5G>A variant in TRAPPC11 was identified by our study in 1 individual with limb girdle muscular dystrophy in the compound heterozygous state, along with another likely pathogenic variant. The variant in TRAPPC11 has been reported in at least 5 Syrian individuals with limb-girdle muscular dystrophy (PMID: 23830518, 31575891), segregated with disease in 3 affected relatives from 2 families (PMID: 23830518), and has been identified in 0.009% (12/129080) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397509418). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic/likely pathogenic by multiple submitters (Variation ID: 60511). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 23830518). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy in an autosomal recessive manner based on the predicted impact of the variant and multiple homozygous occurrences in individuals with limb-girdle muscular dystrophy, as well as co-segregations with disease in multiple affected family members in two families. ACMG/AMP Criteria applied: PP1_strong, PM2, PS3_moderate, PP3, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

7.7

PromoterAI

0.0044

Neutral

(source)

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: -5

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

Publications

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rs397509418

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over