Genetic Variant TRAPPC13:p.Val86Phe (chr5-65637736-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024941.4(TRAPPC13):c.256G>T(p.Val86Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V86I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TRAPPC13
NM_024941.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.24

Publications

0 publications found

Variant links:

Genes affected

TRAPPC13 (HGNC:25828): (trafficking protein particle complex subunit 13) Predicted to be located in cytosol. Predicted to be part of TRAPPIII protein complex. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC13	NM_024941.4	MANE Select	c.256G>T	p.Val86Phe	missense	Exon 4 of 13	NP_079217.2	A5PLN9-1
TRAPPC13	NM_001093755.2		c.256G>T	p.Val86Phe	missense	Exon 4 of 13	NP_001087224.1	A5PLN9-5
TRAPPC13	NM_001243737.2		c.256G>T	p.Val86Phe	missense	Exon 4 of 12	NP_001230666.1	A5PLN9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC13	ENST00000399438.8	TSL:2 MANE Select	c.256G>T	p.Val86Phe	missense	Exon 4 of 13	ENSP00000382367.3	A5PLN9-1
TRAPPC13	ENST00000438419.6	TSL:1	c.256G>T	p.Val86Phe	missense	Exon 4 of 13	ENSP00000409231.2	A5PLN9-5
TRAPPC13	ENST00000505553.5	TSL:1	c.256G>T	p.Val86Phe	missense	Exon 4 of 12	ENSP00000423405.1	A5PLN9-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420486

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707580

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31360

American (AMR)

AF:

0.00

AC:

AN:

39202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25338

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38904

South Asian (SAS)

AF:

0.00

AC:

AN:

81390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087026

Other (OTH)

AF:

0.00

AC:

AN:

58762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.072

MutationAssessor

Uncertain

2.3

PhyloP100

9.2

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.42

Vest4

0.94

MutPred

0.82

Loss of stability (P = 0.1152)

MVP

0.34

MPC

0.80

ClinPred

0.98

GERP RS

5.8

Varity_R

0.77

gMVP

0.80

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over