rs901204498

Variant names:

• chr4-183684817-T-C
• rs901204498
• NM_021942.6:c.1543T>C

Variant summary

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

The NM_021942.6(TRAPPC11):​c.1543T>C​(p.Tyr515His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.92

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 rank	MANE	Protein	UniProt
TRAPPC11	NM_021942.6	c.1543T>C	p.Tyr515His	missense_variant	Exon 15 of 30	ENST00000334690.11	NP_068761.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.1543T>C	p.Tyr515His	missense_variant	Exon 15 of 30	1	NM_021942.6	ENSP00000335371.6
TRAPPC11	ENST00000357207.8	c.1543T>C	p.Tyr515His	missense_variant	Exon 15 of 31	1		ENSP00000349738.4
TRAPPC11	ENST00000512476.1	c.361T>C	p.Tyr121His	missense_variant	Exon 4 of 19	1		ENSP00000421004.1
TRAPPC11	ENST00000505676.5	n.348+811T>C		intron_variant	Intron 5 of 18	1		ENSP00000422915.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461520 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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"). ClinVar contains an entry for this variant (Variation ID: 541341). This variant has not been reported in the literature in individuals affected with TRAPPC11-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 515 of the TRAPPC11 protein (p.Tyr515His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0050	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.24	T;T;D
Sift4G	Benign	0.25	T;T;D
Polyphen		0.29	B;B;D
Vest4		0.96
MutPred		0.48		Loss of ubiquitination at K510 (P = 0.052);Loss of ubiquitination at K510 (P = 0.052);.;
MVP		0.41
MPC		0.62
ClinPred		0.86	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs901204498; hg19: chr4-184605970;