rs148833310

Positions:

• chr4-183679452-C-G
• chr4-183679452-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021942.6(TRAPPC11):​c.931C>G​(p.Leu311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,612,098 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.377

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]

ACMG classification

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=0.16104805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC11	NM_021942.6	c.931C>G	p.Leu311Val	missense_variant	9/30	ENST00000334690.11	NP_068761.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.931C>G	p.Leu311Val	missense_variant	9/30	1	NM_021942.6	ENSP00000335371.6
TRAPPC11	ENST00000357207.8	c.931C>G	p.Leu311Val	missense_variant	9/31	1		ENSP00000349738.4
TRAPPC11	ENST00000505676.5	n.163-756C>G		intron_variant		1		ENSP00000422915.1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000561 AC: 140 AN: 249668 Hom.: 0 AF XY: 0.000585 AC XY: 79 AN XY: 135016

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000677

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000872 AC: 1273 AN: 1459834 Hom.: 0 Cov.: 31 AF XY: 0.000862 AC XY: 626 AN XY: 726260

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000563

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74450

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000715 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.00110

EpiControl AF: 0.000951

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Autosomal recessive limb-girdle muscular dystrophy type R18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.83
MVP		0.36
MPC		0.52
ClinPred		0.074	T
GERP RS		-0.86
Varity_R		0.72
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs148833310; hg19: chr4-184600605;