4-183663883-T-C

Variant summary

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

The NM_021942.6(TRAPPC11):c.16T>C(p.Trp6Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.77

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC11	NM_021942.6	c.16T>C	p.Trp6Arg	missense_variant	2/30	ENST00000334690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.16T>C	p.Trp6Arg	missense_variant	2/30	1	NM_021942.6	P1
TRAPPC11	ENST00000357207.8	c.16T>C	p.Trp6Arg	missense_variant	2/31	1
TRAPPC11	ENST00000505676.5	c.16T>C	p.Trp6Arg	missense_variant, NMD_transcript_variant	2/19	1
TRAPPC11	ENST00000504526.1	n.162T>C		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type R18 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 24, 2021	This sequence change replaces tryptophan with arginine at codon 6 of the TRAPPC11 protein (p.Trp6Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TRAPPC11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.43		Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);
MVP		0.38
MPC		0.67
ClinPred		0.92	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.74
gMVP		0.74

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

Other links and lift over

dbSNP: rs981293069; hg19: chr4-184585036;